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Comments on “Endocrine Disrupting Nonylphenols Are Ubiquitous in Food” There is consensus that endocrine active chemicals, at high doses, may cause developmental, reproductive, or tumorigenic effects (hazard); but, the question of risks associated with xenoestrogens under realistic exposure conditions is still a matter of controversy (1). The research paper by Guenther et al. (2) provides valuable data on the occurrence of 4-nonylphenols (NP) in foods and associated human intake figures for these xenoestrogens. However, the authors did not address the question of risks associated with NP residues in food. This aspect deserves a comment in light of ongoing discussions on endocrine active chemicals: (i) The rather catchy title (2) is suggestive of a major threat for human health because of the mere presence of the weakly estrogenic NP in foods. (ii) The paper refers to NP as .persistent, and .toxic, chemicals that .bioaccumulate,. This creates a picture of close similarity of NP to persistent organic pollutants (POP) but disregards pronounced differences in the toxicokinetics of POPs and NP (1, 3). (iii) The possibility of additional human exposure to NP is raised, but sources (other than food) are not indicated (2). On the other hand, the paper fails to mention that phytoestrogens (i.e., endocrine active chemicals of natural origin) are usually present at much higher dietary levels than synthetic chemicals (4-6). In our view, the reader is left with the impression that ubiquitous NP residues in food will indeed exert adverse effects on humans by disrupting their endocrine system and/ or that there are no concepts to quantitatively assess the associated risks for humans. This calls for a closer look at recent studies with nonylphenols, relevant to human toxicity assessment. The paper by Guenther et al. (2) is the first systematic analysis of NP concentrations in food on the basis of a large number of samples. Along with German food consumption data, this was used to calculate a daily NP intake for adults of 7.5 µg; lower daily intakes of 0.2 and 1.4 µg of NP were calculated for infants fed either breast milk or infant formulas, respectively. These dietary exposures, to be expected for humans, are important when looking at rodent investigations on adverse hormonal effects and estrogenic potency within a wide range of doses. As exemplified in several studies, adverse effects are dependent on dose and hormonal potency of the compound in question. In male rats treated neonatally with high doses of chemicals of different potency (diethylstilbestrol, ethinyl estradiol, genistein, octylphenol, bisphenol A), the magnitude and duration of adverse effects was in fact related to the estrogenic potencies of the test compounds (7). Nagao et al. (8) examined the effects of high doses of nonylphenol (500 mg/kg body wt) and estradiol (2 mg/kg body wt), given sc on postnatal days 1-5 to rats: female rats later showed an altered estrous cycle and abnormal reproductive function, while males treated with NP or estradiol showed normal reproduction. Similarly, neonatal exposure of rats to the phytoestrogen genistein (oral doses of 12.5-100 mg/kg body wt) caused dysfunction of postpubertal reproductive performance as well as abnormal development of gonads in female but not in male rats (9). A recent two-generation study in rats by Nagao et al. (10) with administration of NP by gavage suggests a no observed adverse effect level (NOAEL) 2622
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TABLE 1. MOS Calculation for Nonylphenols NOAEL (two-generation oral rat study (10) F1 generation systemic exposure dose (SED) for humans (2) adults (7.5 µg/d: 60 kg) infants (0.2 µg/d: 6 kg) highest (1.4 µg/d: 6 kg) MOS ) NOAEL/SED for adults for infants
10 mg kg-1 d-1 ) 10 000 µg kg-1 d-1 0.125 µg kg-1 d-1 0.03 µg kg-1 d-1 0.23 µg kg-1 d-1 80 000 43 478-333 333
on reproductive capacity of 50 mg kg body wt-1 d-1 in parent animals and of 10 mg kg body wt-1 d-1 in the next generation. The latter study (10) is particularly interesting with respect to the reported NP levels in German food (2). It is clearly apparent that the figures for human dietary NP intake (7.5 µg/d for an adult or 0.2-1.4 µg/d for infants) are well below the dose of concern on the basis of the results of the effect levels, which are apparent from the rodent studies. Experimentally based NOAEL data are a primary element with regard to human toxicity assessment. In contrast to other approaches, the margin of safety (MOS) methodology of the European Union does not make use of numerical fixed assessment factors: the MOS is calculated by comparing levels of human exposure with the NOAEL from animal experiments. An application of this concept to nonylphenol is easily possible under the condition that hormonal effects or reproductive toxicity are the critical toxicological end point. In the present case, using the lowest NOAEL, the MOS for dietary ingestion of NP in Germany would be higher than 40 000 for infants and 80 000 for adults (Table 1). Another approach to visualize the potential human health impact of environmental estrogens is the hygiene-based margin of safety (HBMOS) concept (11): It integrates mechanistic considerations, exposure scenarios, and potency data for industrial chemicals and phytochemicals (isoflavones) with estrogenic activity. Comparing effects of phytoestrogens and of synthetic environmental estrogens, HBMOS has been defined as the quotient of estimated human daily intakes weighted by the respective relative (rodent) in vivo potencies. HBMOS values thereby provide an estimate of estrogen exposure by man-made chemicals in relation to an existing dietary exposure of phytoestrogens and help to identify compounds that should be given priority for further evaluation (3, 12). HBMOS values have been calculated for nonylphenols and bisphenol A (BPA), and the margin of safety appeared sufficiently high to ensure the absence of a practical risk to human health (11). These first calculations were based on experimental data for uterotrophic potency of these compounds and on previously published exposure estimates (worst-case assumptions). The paper by Guenther et al. (2) now provides much more realistic figures for daily NP intake of consumers. In light of this and new and lower exposure estimates by the European Commission for BPA (13), we have recalculated HBMOS values (12): the present figures, an HBMOS of 2000 and 2500 for NP and BPA (HBMOS for dietary soy isoflavones is by definition equal to 1) indicate an even higher “margin of safety” than previously calculated (11). The estrogenic load to the human organism by these chemicals is clearly insignificant in relation to that imposed by phytoestrogen-rich diets. 10.1021/es020204a CCC: $25.00
2003 American Chemical Society Published on Web 05/03/2003
In summary, the results of two different concepts (MOS and HBMOS) to assess hormonal risks of nonylphenol are principally consistent with each other. It must be concluded that current margins of safety for contemporary nonylphenol exposures are indeed indicative of sufficient safety for the consumer of German foods.
Literature Cited (1) National Research Council. Hormonally Active Agents in the Environment; National Academy Press: Washington, DC, 1999. (2) Guenther, K.; Heinke, V.; Thiele, B.; Kleist, E.; Prast, H.; Raecker T. Environ. Sci. Technol. 2002, 36, 1676. (3) Degen, G. H.; Janning, P.; Wittsiepe, J.; Upmeier, A.; Bolt, H. M. Toxicol. Lett. 2002, 127, 225. (4) Andersson, A.-M.; Skakkebaek, N. E. Eur. J. Endocrinol. 1999, 140, 477. (5) Deutsche Gesellschaft fu ¨ r Experimentelle und Klinische Pharmakologie und Toxikologie. Umweltmed. Forsch. Prax. 1999, 4, 367. (6) Degen, G. H.; Bolt, H. M. Int. Arch. Occup. Environ. Health 2000, 73, 433. (7) Fisher, J. S.; Turner, K. J.; Brown, D.; Sharpe, R. M. Environ. Health Perspect. 1999, 107, 397.
(8) Nagao, T.; Saito, Y.; Usumi, K.; Nakagomi, M.; Yoshimura, S.; Ono, H. Hum. Exp. Toxicol. 2000, 19, 284. (9) Nagao, T.; Yoshimura, S.; Saito, Y.; Nakagomi, M.; Ono, H. Reprod. Toxicol. 2001, 15, 399. (10) Nagao, T.; Wada, K.; Marumo, H.; Yoshimura, S.; Ono, H. Reprod. Toxicol. 2001, 15, 293. (11) Bolt, H. M.; Janning, P.; Michna, H.; Degen, G. H. Arch. Toxicol. 2001, 74, 649. (12) Degen, G. H.; Bolt, H. M. In Menopause: The State of the ArtResearch and Practice; Schneider, H. P., et al., Eds.; Parthenon Publishers: Lancaster, U.K., 2003; Chapter 51, pp 307-311. (13) European Commission, Scientific Committee on Food. Opinion of the Scientific Committee on Food on Bisphenol A; SCF/CS/ PM3936; Final May 3, 2002; EC: Brussel, Belgium; see also http://europa.eu.int/comm/food/fS/sc/scf/index_en.html.
Gisela H. Degen* and Hermann M. Bolt Institute of Occupational Physiology at the University of Dortmund (IfADo) Ardeystrasse 67 D-44139 Dortmund, Germany ES020204A
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