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Eatris.itAnn Ist super sAnItà 2008 | Vol. 44, no. 1: 57-63 Francesca Baldi and Alberto Mantovani
Dipartimento di Sanità Pubblica Veterinaria e Sicurezza Alimentare, Istituto Superiore di Sanità, Rome, Italy Summary. Diet is a significant source of exposure to endocrine disrupting chemicals (EDC); health
risks cannot be excluded, in particular long-term effects in vulnerable groups such as children. However, food safety assessment must also consider the effects of natural food components modu- lating the endocrine system. The scientific evidence on the complex interactions between EDC and food components is still limited. The new EDC-Diet Interactions Database (EDID) within the ISS EDC area (www.iss.it/inte/) aims to stimulate further research in the field of food toxicology: a data- base on international literature’s studies, either on experimental systems and on animal population and humans, easy to consult and periodically updated. Examples of studies contained in EDID are provided concerning EDC with iodine, vitamins and phytoestrogens.
Key words: risk assessment, risk-to-benefit-analysis, toxicology, nutrition, endocrine disrupters, contaminants, Riassunto (Una nuova base di dati sulla sicurezza alimentare: EDID (Endocrine disrupting chemicals
- Diet Interaction Database). L’alimentazione è un’importante via di esposizione ad interferenti endocrini (endocrine disrupting chemicals, EDC), con possibili effetti a lungo termine su gruppi vulnerabili come l’infanzia. Tuttavia la valutazione del rischio in sicurezza alimentare deve anche considerare gli effetti di componenti naturali degli alimenti con potenziali effetti endocrini. Le evi- denze scientifiche per caratterizzare le complesse interazioni fra EDC e componenti alimentari sono ancora limitate. Il nuovo database EDC-Diet Interactions Database (EDID) all’interno dell’area tematica “interferenti endocrini” (www.iss.it/inte/) intende contribuire a sviluppare la ricerca nel- la tossicologia alimentare. EDID comprende articoli internazionali, riguardanti sistemi sperimen- tali, popolazioni animali e l’essere umano, di facile consultazione ed aggiornata periodicamente. Vengono illustrati esempi di studi presenti in EDID riguardanti le interazioni di EDC con iodio, vitamine e fitoestrogeni.
Parole chiave: valutazione del rischio, analisi rischio-beneficio, tossicologia, alimentazione, interferenti endo-crini, contaminanti, fitoestrogeni.
tive substances may modulate the endocrine system Endocrine disrupting chemicals (EDC) are an het- function, from trace elements such as iodine, which erogeneous group of substances present in the diet are also essential micronutrients  to the numerous and environment able to modify endocrine home- group of “phytoestrogens”. Phytoestrogens are sub- ostasis, in particular steroid and thyroid hormones; stances present in plants that may interact with es- therefore reproductive health and developing life trogen receptors; examples include genistein, an iso- stages are the most susceptible targets . EDC flavone found in soy, as well as less well-known com- interact with nuclear receptors or with enzymes pounds present in different grains and fruits, such responsible of synthesis or transportation of hor- as daidzein, quercetin, resveratrol, lignans, etc. . mones; they include persistent contaminants (e.g., EDC arouse concern because of their potential for dioxins, polychlorinated biphenyls), compounds both long-term, multiple-target effects on vulnerable used in plant and/or animal production (e.g., dicar- lifestages as well as for general population exposure boxmides, triazoles) and compounds found in indus- associated with the bioaccumulation capability, and/ trial as well as consumer products (e.g., bisphenol or to widespread diffusion of different compounds A, several phthalates, polybrominated flame retard- [1, 2]. Indeed, EDC exposure in the early lifestages is ants) . Endocrine-active chemicals are not con- strongly suspected for the reproductive health dete- fined to xenobiotics. Indeed, many natural bioac- rioration observed in many industrialized Countries Address for correspondence: Alberto Mantovani, Dipartimento di Sanità PubblicaVeterinaria e Sicurezza Alimentare, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail: email@example.com.
Francesca Baldi and Alberto Mantovani . Consequently EDC are one of the chemical con- conception of food toxicology cannot consider diet tamination problems that drew great attention by just as an exposure source of external harmful sub- the scientific community and public opinion. This stances. Contaminants such as EDC may interact is reflected, at European level, by the novel devel- with the same metabolic pathways as natural food opments of testing strategies, especially in the field components such as polyunsaturated fatty acids, of reproductive and developmental toxicology , trace elements, vitamins and other bioactive sub- as well as by the many research projects on EDC stances (e.g. polyphenols) that cannot be consid- . A specific task force on testing and assessment ered nutrients as there is no recognized deficiency. of EDC has also been set up within the chemical Dietary habits are related to socioeconomic status, programme of the Organisation for Economic Co- cultural and religious factors, individual choices operation and Development (OECD) . Due to the (e.g. vegetarianism/veganism); in their turn dietary high and up-to-date relevance of EDC research to habits may have a most important impact on the the fields of food and environmental safety as well intake of either nutrients and contaminants. For in- as of preventive medicine, the Istituto Superiore di stance, the changing dietary habits in Italy lead to a Sanità (ISS) has launched since 2002 a dedicated lower intake of specific vitamins (folic acid, B6 and website, that is updated weekly, with a full English E) as compared to that expected in the traditional version and a special interest to collect information “Mediterranean diet” ; also, greater exposure on ongoing Italian research as well as on emerging to persistent EDC is associated with the high con- sumption of fatty foods of animal origin . Thus, for specific food commodities a balanced evaluation is needed about contaminant-associated risks and EndocRInE dISRuptIng
nutritional benefits. The most up-to-date example is chEMIcAlS, dIEt And nutRIEntS
represented by salmonids and other seafood, both Diet is a particularly significant source of exposure wild and farmed, that are a useful source of nu- to EDC for the general population. The suspicious- trients such as polyunsaturated fatty acids as well ness of EDC assumption via diet is a source of con- as a major source of exposure to EDC and other cerns and “alarms” more or less justified for consum- contaminants able to bioaccumulate such as meth- ers’ health. One major issue is the “cocktail” effect. ylmercury; therefore, evidence might justify recom- Residue monitoring data in Europe indicate that mendations to increase as well as to reduce fish con- regulatory limits are exceeded in a minority of cases, sumption, quite an uneasy situation for risk manag- at least concerning compounds for which such limits ers and public health policy makers . Indeed, as do exist, e.g. pesticides ; however, one cannot rule response to several pollution “alarms” in northern out altogether additivity of different EDC present in Countries, the European Food Safety Authority whole diet at low-level, but hitting the same targets, (EFSA) issued in 2005 its first risk-to-benefit opin- e.g. nuclear receptors . Furthermore, it is not just ion about consumption of wild and farmed fish the daily dose that matters. Many EDC can bioac- . The EFSA document concluded that decreas- cumulate, especially in body lipids, forming a “body ing fish consumption (and its nutritional benefits) is burden” of contaminants of different origin that can not necessary in Europe; in the meanwhile, recom- include dioxins, banned compounds that still persist mendations included to continue the monitoring of in the environment (polychlorinated biphenyls, chlo- contaminants in edible fish as well as the support to rinated pesticides and their metabolites), and bromi- development of novel aquaculture feeds, less liable nated flame retardants . Other compounds, even to contamination. Most important, effects of con- though less persistent, may nonetheless concentrate taminants and of natural food components are not in food chains and/or body tissues, thus adding to running in parallel; in most instances, they interact the overall EDC internal burden; examples are on the same pathways and targets. It can be inferred phthalates  and organotins . Thus, the po- that a well-balanced diet, with a good intake of anti- tential risk is less related to the contamination of a oxidants, may be partly protective towards the ef- single food commodity than to the long term intake fects of toxic exposures. The interactions may not be through the overall diet, whose impacts on the total always so straightforward, however, as several nutri- EDC body burden as well as on chronic health ef- ents and bioactive components can exert adverse ef- fects are incompletely known. Another issue to be fects. An example are phytoestrogens, that can offer considered in risk assessment is different vulnerabili- a protective effect against some hormone-dependent ties within the general population: concerning EDC, cancers, as well as postmenopausal osteoporosis, those best recognized are related to age and gender. but may also interfere with receptor-mediated signal For instance, children can be considered as a group transduction (e.g. by inhibiting protein kinase) and at higher risk, due to higher relative consumption of DNA replication, which might also lead to promot- food and water as compared to adults as well as to ing the proliferation of some cancer cells . One the ongoing functional development of reproduc- cannot even exclude that high phytoestrogen dosage tive, nervous and immune systems .
may have additive effects associated with contami- However, other factors that can modulate vulner- nants that target the same receptors. Up to date, ability deserve adequate consideration. The modern scientific data available on interactions between xe- nobiotics and “natural” substances in food are still are not typical EDC, while investigations on dioxins meagre, in spite of the relevance that such topic may and PCB took course years before the widespread have in the food safety and prevention fields. diffusion of the EDC concept. A simple, general keyword like “endocrine” matched with nutrient- relevant keywords (“trace element”, “vitamin”, nu- EdId: EndocRInE dISRuptIng chEMI-
trient” or more specific ones) can be more effective, cAlS - dIEt IntERActIon dAtABASE
although it obviously lacks specificity and requires The new EDC - Diet Interactions Database (EDID) careful selection of the really EDID-relevant papers. within the ISS EDC website (www.iss.it/inte/edid/cont.
Currently, updating has to be performed through a php?id=110&lang=2&tipo=17), started in 2006, is selection of matched keywords (e.g., “PCB AND the first database dedicated to interactions between vitamin”, “Pesticide” AND “phytoestrogen”, etc.), EDC and nutrients; currently it contains more than extracting the relevant papers and the “fishing” col- 300 items. For setting and updating the database the lection of related papers. Although such approach terms “EDC” and “diet” needed definition. EDC is has been satisfactorily effective in the first launching taken in its broad sense, as in the 1996 Weighbridge phase of EDID, that will end 24 months after start, definition adopted in Europe as a chemical that can the elaboration of a more systematic approach to induce adverse effects on the health of an organism literature search will be implemented in the follow- or of its progeny through endocrine mechanisms (see the ISS EDC website homepage www.iss.it/ inte/?lang=2; whereas “diet” includes all nutrients, either macro- (protein, glucose, etc.) or micronutri- ExAMplES oF EdId topIcS
ents (vitamins, trace elements), as well as bioactive The following paragraphs deal with some of the compounds that can be naturally present in foods, main topics that can be found in the EDID database.
besides any man-made addition. EDID aims to be a contribution for stimulating further research in the Iodine, thyroid function and EDC
field of xenobiotics-nutrients interactions. EDID is Iodine is the main determinant of thyroid develop- conceived primarily as a database on studies pub- ment and function; some food commodities of ani- lished on international peer-reviewed literature, ei- mal origin, namely seafood and milk, are the main ther on experimental systems in vitro/in vivo, animal dietary sources, nevertheless subclinical iodine de- populations (both wild and farmed) and humans. ficiency in humans and farm animals is still a com- However, some relevant reports available on the web mon problem in many areas, including Europe . and issued by national or international Agencies Thyroid is also an emerging target for EDC; it may are also included, such as the already quoted EFSA be reasonable to hypothesize that a low iodine sta- opinion on fish consumption . EDID aims at be- tus would enhance the susceptibility to thyrostatic ing a user-friendly database; it utilizes DSpace which xenobiotics. Yet, it is unfortunate that only a limited is one of the first open source software platforms to number of papers till now deal with the relationship store, manage and distribute its collections in dig- between iodine status and EDC effects. Somewhat ital format (http://dspace.iss.it/dspace/). Different unexpectedly phthalates, widespread plasticizers search criteria may be set, namely: a) words present that rise concern mainly because of their antian- in the article’s title; b) keywords not present in the drogenic effects, can modulate basal iodide uptake article’s title, including s, nutrients, animal species, mediated by the sodium/iodide symporter in thyroid targets (tissues, organs, enzymes, receptors etc.); follicular cells in vitro . Interestingly, the effect usually four such keywords are selected for each was not a general effect of phthalates and was inde- paper; c) the author’s name (the first three if more pendent from cytotoxicity; dibutyl phthalate was the than three authors are present); d) the article’s re- most cytotoxic out of the six compounds tested but lease year. Due to current copyright regulations, it did not modulate iodide uptake. Phytoestrogens most documents present in EDID are available only may also deserve more investigation as a study show as abstracts: however, the corresponding author’s that many of them may interfere with iodination of address and full journal reference enables to easily thyroid hormones: some (e.g., naringenin, and quer- recover the full paper, when needed.
cetin, which contain a resorcinol moiety) are direct EDID is periodically updated. The current lack and potent inhibitors of thyroid peroxidase, where- of standard keywords or search tools for papers on as others (myricetin, naringin) showed noncompeti- toxicant-nutrient interactions makes it necessary tive inhibition of tyrosine iodination with respect to perform an expert-based, case-by-case “fishing” to iodine ion and biochanin A acted as an alternate search. For instance, the keywords “endocrine dis- substrate for iodination . Indeed, a Czech bio- rupter”, “endocrine disruptor” or “endocrine dis- monitoring study in children without over hypothy- rupting chemical” do not catch many papers on di- roidism showed a modest but significant adverse oxins, polychlorinated biphenyls or phytoestrogens, relationship of serum concentrations of genistein, although such keywords do perform more effec- with markers of thyroid function, while no signifi- tively with chemicals like phthalates, bisphenol A or cant association was found for another isoflavone, pesticides; the reason might be that phytoestrogens daidzein. However, since even small differences in Francesca Baldi and Alberto Mantovani phytoestrogen intake were related to thyroid func- P450 (CYP) 1A1, that in its turn may enhance the tion, this might have an impact in children popula- toxic effects of TCDD. Several studies indicated that tions where iodine intake is insufficient . concurrent supplementation of vitamin A could in- hibit CYP1A1 activity (measured as ethoxyresoru- Oxidative stress, antioxidant vitamins and EDC
fin-O-deethylase [EROD] activity). In particular, in Activation of nuclear receptors such as the es- mice orally treated with TCDD the concurrent ad- trogen receptor alpha is closely related to redox ministration of vitamin A reduces liver damage and status and oxidative stress pathways . Indeed, the specific markers of TCDD action, namely the one of the major clusters within EDID includes augmented EROD activities, CYP1A1 expression, papers showing that antioxidants such as vitamins and AhR mRNA expression . These findings C and E exert a protective role towards the effects suggest a relationship between vitamin A depletion of EDC such as phthalates and PCB. Two exam- and TCDD effects at molecular levels, at least in ples are given. Di-(2-ethylhexyl) phthalate (DEHP) liver tissue; however, the role of retinoic acid as a may be the most potent EDC among phthalates target within the wide range of adverse dioxin-in- and it is surely the most thoroughly investigated; duced effects still needs clarification. Organotins do the compound can interfere with steroid synthe- not bind to steroid nuclear receptors, but may alter sis pathways by interacting with the Pregnane-X steroid biosynthesis . Tributyltin chloride and nuclear receptor . DEHP can severely disrupt triphenyltin hydroxide, bind specifically to the RXR spermatogenesis in adult rodents; however such in human choriocarcinoma cells; binding elicit tran- effects are reversible upon discontinuation of the scriptional activation of endocrine signalling, e.g. treatment. Supplementation with vitamins C and aromatase, but not the retinoic acid pathways . E can protect the seminiferous epithelium from Thus, more research on the interactions of EDC DEHP effects; moreover, the supplementation with acting through different mechanisms with retinoic both vitamins after the treatment significantly ac- celerated regeneration of the testis epithelium . Non-dioxin like PCB can alter endocrine homeos- Phytoestrogens and xenobiotics
tasis through several, mainly non-receptor medi- Due to their pleomorphic biological effects, in- ated, mechanisms. The PCB mixture Aroclor 1254 cluding some potentially adverse ones, phytoestro- was tested on cultured chicken embryo hepatocytes gens could be considered a sort of “natural EDC” with and without vitamin E, vitamin C and vitamin [4, 19]. Most attention has been concentrated on A, alone and in combination. Aroclor 1254 caused the soy phytoestrogen genistein, possibly the most irreversible damage to cell membrane integrity and potent phytoestrogen; however, the overall dietary increased cellular lipid peroxidation, whilst reduc- intake of phytoestrogens may be significant in ing glutathione levels and superoxide dismutase Europe, even though lower than in Eastern Asia activities. The vitamins, either alone and in combi- . Therefore the interactions between phytoes- nation (A+E and C+E, apparently not A+C) sig- trogens and EDC could represent a major topic of nificantly attenuated the toxic effects; the findings interest, due to combined presence in diet and pos- in this system also suggest that lipid peroxidation sible sharing of biological targets. Yet, periodical may be a key event in PCB toxicity . Still most EDID updating has led to include less than 20 pa- studies on EDC and antioxidant vitamins show a pers on such issue till now. As phytoestrogens may protective effect, but only few attempts to elucidate have beneficial effects on human health, they have mechanisms. Also, it would be interesting to have been also hypothesized to compete with estrogenic more comprehensive data on the combined impact EDC, thus exerting a protective action. Indeed, on EDC effects of dietary antioxidants, in the pro- flavonoids (daidzein, genistein, quercetin, and portion and amount provided by the different di- luteolin) can suppress the induction of the prolif- eration-stimulating activity of estrogen-like acting EDC (4-nonylphenol, bisphenol A, and the PCB 4- EDC and vitamin A
dihydroxybiphenyl) in MCF-7 cells . The effect Retinoic acid is the internal form of vitamin A of mixtures containing 17beta-estradiol, 17alpha- interacting with the nuclear receptors RAR and ethinylestradiol, genistein, and estrogenic EDC RXR; all-trans-retinoic acid and 9-cis-retinoic acid (the plastic additive bisphenol A, and the anionic are the natural ligands for RAR and RXR, respec- detergent by-products 4-nonylphenol, and 4-tert- tively. In its turn, retinoic acid pathways cross-talk octylphenol.) was less than additive when assessed with that of the aryl hydrocarbon receptor (AhR), through the proliferation of estrogen-dependent the direct cell target for dioxins and dioxin-like MCF-7 human breast cancer cells; the partly ana- compounds . Thus, it is relevant to investigate tagonistic interaction was observed in particular the specific interactions between EDC and vitamin between the other compounds, including genistein, A metabolism. However, up to now only a few have and 4-nonylphenol and 4-tert-octylphenol . been clearly shown to interfere with this pathway. In some cases no interaction can be observed: the The most toxic dioxin, 2,3,7,8-tetrachlorodibenzo- combined treatment with genistein did not modu- p-dioxin (TCDD) is a potent inducer of cytochrome late the in vitro effects on human astroglial cells of two persistent EDC, the polybrominated flame polyborominated flame retardants or organotins retardant PBDE-99 and the PCB mixture Aroclor are much less represented, even though their cur- 1254 . The available findings in vivo provide a rent exposure levels do create concerns for food and more complex picture. Genistein and the estrogenic environmental safety [11-13]. It is also somewhat chlorinated insecticide methoxychlor were tested on surprising that a number of papers on toxicant rats alone or in combination, to assess possible ef- (including EDC)-nutrient interactions were issued fects on immune function, a potential critical target some 10-20 years ago, i.e., before the start or the for EDC that is still somewhat underscored by the full development of interest and research on EDC. available literature. A possible additive effect was Such papers, even though valuable, obviously can- seen in the parental generation on the reduction of not provide the in-depth information that could be relative spleen and thymus weight as well as, to a supported by the novel research tools of molecu- lesser extent, of weight gain. In the F1 generation lar toxicology [27-33], and that is required by the the combined effect of genistein (at dose levels low- conceptual framework of EDC risk assessment. er than those effective in the parental generation) Nevertheless, apparently the topic did not draw too and methoxychlor had a significant detrimental im- much attention from risk assessment or research- pact on the total number of thymocytes as well as funding agencies; this situation may rapidly change, on the different CD4-CD8 subclasses . New in- due to food safety becoming a cutting-edge topic for sights are provided by a recent paper using estrogen both research and public health as well as the new reporter (ERE-tK-Luciferase) male mice. Genistein developments of risk-to-benefit analysis. Indeed, as can partially accumulate in body fat depots where it other topics become “fashionable”, a new output may persist for weeks at functionally active levels; of papers is expected, e.g. on risk-to-benefit analy- following fasting genistein is released from adipose sis of contaminants and nutrients in seafood [17, tissue in the circulation and can modulate the ac- 18]. Other shortcomings of the database reflect tions of either estradiol and persistent EDC in liver more wider knowledge gaps. For instance, the soy and testis with tissue-specific features. In particular isoflavone genistein is the only phytoestrogen that genistein reversed the antiestrogenic action of beta- is thoroughly investigated, even though other com- benzene-hexachloride in the tesis and of o,p’-DDT pounds, e.g. lignans, may have a higher intake from in the liver, whereas it had an additive effect with European populations . Most important, there the ER agonist p,p’-DDT in the liver . Thus, the are still a limited number of human epidemiologi- available data can only indicate that interactions cal studies that concurrently investigated mark- between phytoestrogens and EDC can be important ers of toxicant exposures and of nutrient intake. but also that they cannot simply explained in terms Examples include: the assessment of long-term per- of additivity or antagonism; as a consequence the chlorate exposure thorough drinking water, thyroid dietary intake of phytoestrogens cannot be consid- markers and iodine in urine and breast milk that ered per se a protective factor towards exposures to has been carried out in Northern Chile and found environmental EDC. More research should be war- no significant impact ; the intervention study ranted on phytoestrogens other than genistein as with folic acid, carried out on adults from an ar- well as biomonitoring studies in humans on both senic-polluted area of Bangladesh, indicating that ohytostrogens and contaminants using appropriate folic acid supplementation enhances arsenic meth- ylation, hence metabolism and excretion, in sub- jects with low plasma folate . Therefore, a full assessment of EDID content, development accessi- concluSIonS
bility and usability will be performed after the first EDID represents a novel instrument for research in food toxicology, that will be implemented and in- Yet, notwithstanding the unavoidable problems of creased as the EDID issues will receive increasing a starting phase, increasing evidence supports the attention from research and risk assessment. The hypothesis originating EDID, i.e., that diet is a sub- shortcomings of EDID are these of the available stantial risk modulator of EDC-related health risks literature. As no systematic projects or actions do and that an evidence-based assessment of the com- exist yet on the interface between EDC and dietary plex EDC-diet interactions is required [31, 33, 34]. components, it is unavoidable that the presence of Thus, in perspective EDID may provide important a given topic is related to the interest (and success) information and tools also to preventive medicine, of a given research group. Examples, as mentioned namely i) nutritional markers that are relevant to above, are the paucity of studies on iodine uptake the susceptibility to specific EDC or EDC groups modulation by EDC and the comparative abun-  and ii) dietary interventions or supplementa- dance of papers investigating the putative protec- tion that may be performed with population groups tive role of the antioxidant vitamins C and E. Also, exposed to EDC that interfere with metabolism of a large proportion of papers present in EDID deal with “old” contaminants such as dioxins, PCB and Finally, as pointed out by the EFSA , new ap- to a lesser extent heavy metals; other, more recent proaches are needed in food safety, encompassing EDC such as phthalates, bisphenol A, nonylphenol, also a comprehensive of the health impact – either Francesca Baldi and Alberto Mantovani detrimental and/or beneficial – of a given food com- Acknowledgements
modity. When required, decision makers should be EDID has been elaborated within the frame of the ISS special provided with a balanced assessment of toxicologi- Project “Interferenti Endocrini” (resp. A. Mantovani) as well as cal and nutritional risks and benefits; thus the devel- of the 6th FP Network of Excellence CASCADE (www.casca- opment of a knowledge basis on toxicant-nutrient interactions is most critical for a science-supported Accepted on 16 December 2007.
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M5045 Lantus_CMEFacGde_Pad 9/27/06 1:40 PM Page 1**Tony_Weir **MacHD: Tony Weir-Jobs:Current Jobs: M5045 Lantus: Starting insulin: • It is important to monitor your blood sugars closely as you patient guide • Record your blood sugars every day before breakfast and2–3 other times every day; test before meals unless your• You and your doctor have decided that you will start • Reco