Pharmaceutical Science Related

846 Mini-Reviews in Medicinal Chemistry, 2010, 10, 846-855

1389-5575/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.

Endocrine Disruptors and Human Health

G. Latini* ,1,2

, G. Knipp 3 , A. Mantovani

4 , M.L. Marcovecchio

5 , F. Chiarelli

5 and O. Söder


1 Division of Neonatology, Perrino Hospital, Brindisi, Italy;

2 Clinical Physiology Institute, National Research Council of

Italy (IFC-CNR); 3 Purdue University, Department of Industrial and Physical Pharmacy,575 Stadium Mall Dr., West

Lafayette, IN 47907; 4 Food and Veterinary Toxicology Unit, Dept. Veterinary Public Health and Food Safety, Istituto

Superiore di Sanità, Viale Regina Elena, 299 00161, Rome; 5 Department of Pediatrics, University of Chieti, via dei

Vestini 5, Chieti, Italy; 6 Department of Women’s and Children’s Health, Paediatric Endocrinology Unit, Karolinska

Institute and University Hospital, S-17176, Stockholm, Sweden

Abstract: Endocrine-disrupting chemicals (EDCs) are a group of diversely natural compounds or synthetic chemicals that

can interfere with the programming of normal endocrine-signalling pathways during pre- and neonatal life, thus leading to

adverse consequences later in life. In addition, early life exposure to EDCs may alter gene expression and consequently

transmit these effects to future generations.

Keywords: Endocrine-disruptors, environment, endocrine system, phthalates, pregnancy, neonate, fetal.


Endocrine-disrupting chemicals (EDCs) are a large and increasing group of diversely natural compounds or synthetic chemicals present in the environment that include persistent halogenated pollutants, such as polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and me- tabolites, industrial compounds, such as bisphenol A (BPA), alkylphenols and phthalate acid esters, as well as pharmaceu- ticals, pesticides, such as chlorpyrifos, fungicides including vinclozalin and phytoestrogens.

Man-made EDCs range across all continents and oceans. EDCs, which are typically present as complex mixtures and not as single substances, may mimic, block or modulate the synthesis, release, transport, binding, metabolism and/or elimination of natural endogenous hormones in wild animals and humans [1]. In particular, EDC may interfere with hor- monal signalling systems and alter feedback loops in the brain, pituitary, gonads, thyroid, and other components of the endocrine system.

Growing evidence shows that EDC may also modulate the activity/expression of steroidogenic enzymes and steroi- dogenic pathways [2-5].

In addition, EDC can also promote activation of meta- bolic sensors, such as the peroxisome proliferator-activated receptors (PPARs) [6]. As a consequence, there is an increas- ing concern worldwide on the potential adverse effects of ED on human health, although their impact on human be- ings’ health is not yet clear.

However, endocrine signalling pathways play an impor- tant role during prenatal differentiation; thus, developing organisms may be particularly sensitive to ED effects. In


*Address correspondence to this author at the Division of Neonatology,

Ospedale A. Perrino, s.s. 7 per Mesagne, 72100 Brindisi, Italy;

Tel: +39-0831-537471; Fax: +39-0831-537861;

fact, scientific evidence indicate that exposure to ED during critical periods of development can induce permanent changes in several organs, including molecular alterations, although the consequences of this disruption may not appear until later [7-11]. The mechanisms by which ED exert their action remain largely unclear; however, many ways have been identified by which ED can affect signal transduction systems [12].

Early life exposures to EDCs may alter gene expression via non-genomic, epigenetic mechanisms, including DNA methylation and histone acetylation, thus interfering with the germ-line. By contaminating the environment with ED hu- man race might be permanently affecting the health of sub- sequent generations [13-15]. Within the broad ED topic we have focussed on specific issues, selected since they are highly relevant to the up-to-date assessment of potential hu- man health risks from ED exposure.



Diet is a significant source of exposure to ED for the general population, as well as a source of concern for con- sumers’ health. One major issue is the “cocktail” effect: one cannot rule out additivity of different ED present in whole diet at low level, but hitting the same targets, e.g. nuclear receptors [16]. Furthermore, it is not just the daily dose that matters. Many ED can bioaccumulate in lipid fraction of tissues, originating a mixture “body burden” of contaminants of different origin that can include dioxins, polychlorinated biphenyls, chlorinated pesticides and their metabolites, as well as brominated flame retardants [17]. Other compounds may also concentrate in food chains, thus adding to the over- all ED burden, e.g., organotins [18]. However, the modern conception of food toxicology cannot consider diet just as an exposure source of external harmful substances. Contami- nants such as ED may interact with the same metabolic pathways as natural food components such as polyunsatu-



Endocrine Disruptors and Human Health Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 9 847

rated fatty acids, trace elements, vitamins and other bioactive substances (e.g. polyphenols) that cannot be considered nu- trients as there is no recognized deficiency [19]. Dietary hab- its are related to socioeconomic status, cultural and religious factors, individual choices (e.g. vegetarianism/veganism); and dietary habits themselves may have the most important impact on the intake of both nutrients and contaminants. For instance, greater exposure to persistent ED is associated with the high consumption of fatty foods of animal origin [20, 21]. Thus, for specific food commodities a balanced evalua- tion is needed about contaminant-associated risks and nutri- tional benefits. A relevant example is represented by salmon- ids and other seafood, a useful source of nutrients such as polyunsaturated fatty acids as well as a major source of ED and other bioaccumulating contaminants, such as meth- ylmercury. Evidence might justify recommendations to in- crease as well as to reduce fish consumption, quite an uneasy situation for risk managers: decreasing fish consumption (and its nutritional benefits) may not be necessary in Europe, but monitoring of contaminants in edible fish should be con- tinued, as well as the development of novel aquaculture feeds, less liable to contamination [22].

Most important, effects of contaminants and natural food components may interact on the same pathways and targets. The outcomes of interactions may be complex, depending on dose and targets; e.g., phytoestrogens can protect against some hormone-dependent cancers, as well as postmeno- pausal osteoporosis, but may also interfere with receptor- mediated signal transduction (e.g. by inhibiting protein kinase) and DNA replication [23]. Up to date, scientific data available on interactions between xenobiotics and “natural” substances in food are still limited; below, some relevant examples are provided

Iodine and ED

Iodine is the main determinant of thyroid development and function; seafood and milk are the main dietary sources. Subclinical iodine deficiency is still a common problem in many areas, including Europe [24]; thyroid is also increas- ingly recognized as a major target for ED, including newly recognized ones, such as organpophopsphorus insecticides [25]. Yet, only a few papers target low iodine status in rela- tion to susceptibility to xenobiotics. Somewhat unexpectedly phthalates, the widespread plasticizers known mainly as antiandrogens, can modulate basal iodide uptake mediated by the sodium/iodide symporter in thyroid follicular cells in vitro: the effect was not shared by all phthalates and was independent from cytotoxicity [26]. Many phytoestrogens may interfere with iodination of thyroid hormones. Some (e.g., naringenin, and quercetin, which contain a resorcinol moiety) are direct and potent inhibitors of thyroid peroxi- dase, others (myricetin, naringin) show noncompetitive inhibition of tyrosine iodination with respect to iodine ion, whereas biochanin A may act as an alternate substrate for iodination [27]. A Czech biomonitoring study in children also indicated an adverse effect of genistein on thyroid func- tion [28]. The drinking-water contaminant perchlorate inhib- its thyroidal iodide uptake; however, iodine-deficient female rats were more resistent to the inhibition of iodine absorption from perchlorate exposure than normal rats [29]. Thus, the

interaction between iodine and some thyroid-targeting ED may be less straightforward than expected.

Phytoestrogens and the “xeno”ED

Due to their pleomorphic biological effects, phytoestro- gens are a sort of “natural ED”, whose overall dietary intake of phytoestrogens may be significant also in Europe [23, 30, 31]. Flavonoids (daidzein, genistein, quercetin, and luteolin) can at least partly antagonize the proliferation-stimulating activity of synthetic estrogenic ED in estrogen-dependent MCF-7 human breast cancer cells: thee ED included anionic detergent by-products alkylphenols, plastic additive bisphe- nol A, and the PCB 4-dihydroxybiphenyl [32, 33]. These findings suggest that phytoestrogens can compete with es- trogenic ED on shared biological targets, thus exerting a pro- tective action . In other models no interaction was observed: genistein did not modulate the effects on human astroglial cells by two persistent ED, the polybrominated flame retardant PBDE-99 and the PCB mixture Aroclor 1254 [34]. As it is sometimes the case, in vivo studies provide a more complex picture. Genistein and the estrogenic chlorinated insecticide methoxychlor had an additive impact on both immune function and immune functional development in rats; the developing thymus appeared as a sensitive target of combined exposure [35]. In estrogen reporter (ERE-tK- Luciferase) male mice genistein modulated the actions of both estradiol and persistent ED in liver and testis with tis- sue-specific features: the antiestrogenic action of beta- hexachlorocyclohexane in the testis and o,p’-DDT in the liver was antagonized, whereas genistein had an additive effect with the ER agonist p,p’-DDT in the liver [36]. Two predefined mixtures of phytoestrogens and synthesis ED were tested in the uterotrophic assay on prepubertal rats: the composition of each mixture (what chemicals and to what amount) was based on human exposure data. The phytoes- trogen mixture did elicit an uterotrophic response, whereas the synthetic one has no effect itself nor an additive effect with phytoestrogens, possibly because of exposure levels too low [37]. The combined exposure to estrogenic and antian- drogenic ED is suggested as a potential risk to male repro- ductive development. Genistein and the antiandrogenic fun- gicide vinclozolin, alone or in combination, were investi- gated concerning the induction of hypospadias in mice: the incidences were 25%,, 42% and 41% for genistein, vinclo- zolin and combined treatment, respectively, indicating a less than additive effect [38]. On the other hand, genistein, as well as the methyl donor folic acid, both antagonized the DNA hypomethylating effect of bisphenol A in mouse em- bryos [39]. The available data indicate that interactions be- tween phytoestrogens and ED can be important, but cannot simply explained in terms of additivity or antagonism; in- deed, additivity and antagonism may vary, depending on the chemicals, endpoints and lifestages.

ED and Vitamin A Pathways

Retinoic acid is the internal form of vitamin A interacting with the nuclear receptors RAR and RXR, whose natural ligands are all-trans-retinoic acid and 9-cis-retinoic acid, respectively. Retinoic acid pathways cross-talk with those of the aryl hydrocarbon receptor (AhR), the direct cell target for dioxins and dioxin-like compounds [40]. Dioxins are potent



848 Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 9 Latini et al.

inducers of cytochrome P450 (CYP) 1A1, that in its turn may enhance the dioxin effects; the concurrent supplementa- tion of vitamin A inhibits CYP1A1 activity in dioxin- exposed mice, reducing liver damage as well as CYP1A1 and AhR mRNA expression [41]. Mice lacking retinoid binding proteins were especially responsive to dioxin- induced liver retinoid depletion, intracellular retinoid bind- ing protein I being the main factor. RAR- and RXR- knockout mice were essentially sensitive as wild-type mice, with the exception of RXRbeta-/- mice which showed no decrease in hepatic Vitamin A concentration; this suggest a possible role of RXRbeta in dioxin-induced retinoid disrup- tion [42]. Retinoid storage and metabolism were also dis- rupted in female rats of two strains with different dioxin sen- sitivity (Long-Evans and Han/Wistar) [43]. Comparison of dioxin effects on liver retinyl palmitate in AhR+/- and AhR- /- mice support disruption of retinoid homeostasis as a pri- mary AhR- mediated mode of action of dioxin-like chemi- cals [44]. Retinoid pathways can be a critical target also for polybrominated diphenyl ethers: in rats treated orally with pentaBDE-71, decrease of hepatic apolar retinoids was the most sensitive effect, together with reduced thyroid hormone [45]. These studies might also hint to vitamin A deficiency as a susceptibility factor towards some persistent ED.

Although the portfolio of scientific evidence is still quite limited, several other examples can be retrieved from the Endocrine disrupting chemicals – Diet Interaction Database – EDID, the only dedicated database available on ED-nutrient interactions [19]. One further instance is the general protec- tive action elicited by “antioxidant” vitamins C and E to- wards the effects of several EDs, including dioxin-like poly- chlorinated byphenyls (PCB) and phthalates; indeed, several ED-related modes of action seem to eventually lead to in- creased oxidative stress [46]. Overall, new evidence on in- teractions between ED and natural food components may disclose new insights on food-related factors modulating vulnerability as well as on nutrient intake as support to risk prevention and/or risk reduction strategies.



Maternal exposure to EDCs has been demonstrated to be a significant reason for increases in adverse pregnancy and fetal outcomes. The placenta protects and nourishes the fetus by regulating nutrient and xenobiotic homeostasis between the maternal and fetal compartments. As discussed below, xenobiotics that can affect this placental homeostatic control may lead to abnormal fetal development by altering fetal exposure to toxic compounds and/or nutrient homeostasis [65, 66, 69]. An important aspect of this review is to high- light some areas in which EDCs have drawn considerable attention due to the many potential fetotoxic effects, which may be caused upon in utero exposure. For example, recent evidence suggests a link between EDC exposure and the fetal origins of neurological impairment that cannot be ig- nored even though their mechanistic basis is not well under- stood [47-51]. EDCs are hypothesized to induce functional and/or structural changes in specific neuroendocrine path- way(s), effects being largely dependent upon the phase (ges- tational time) and level of exposure [52]. In addition, the potential for additive or synergistic effects of low dose com-

binations of EDCs are not well established and require con- siderable investigation. [53]. Moreover, the role of other factors including diet, exercise and genetics has not been well characterized, adding to the difficulty in delineating the role of EDCs on neurodevelopment. Finally, the pharma- cokinetic and pharmacodynamic relationships for EDCs dif- fer and there exists a potential for placental and fetal accu- mulation not accurately measured in maternal plasma [52, 54]. For example, a recent study revealed that when both newborns and adults are exposed to the same bisphenol A (BPA) levels, newborns retain up to 3 times more than adults [55].

BPA is an EDC due to its ability to interact with estrogen receptor (ER and ) isoforms, androgen receptors (AR), and possessing a high affinity for the estrogen related recep- tor (ERR ) during mammalian brain development [56]. BPA eluted from polycarbonate drinking bottles was demon- strated to exert an estrogenic like neurotoxic effect in devel- oping cerebellar neurons [49]. BPA has also been demon- strated to alter fetal neurodevelopment through thyroid hor- mone (TH) pathways, as recently in a TH-dependent den- dritic Purkinje cell development in a murine cerebellar cul- ture assay [51, 57].

BPA is metabolized into BPA glucuronide, which is hormonally inactive, and excreted via the urine with a half- life below 6 hours [58]. Despite the rapid metabolism, the U.S. CDC have found BPA levels in 95% of all human urine samples tested, suggesting broad and continuous BPA expo- sure [59, 60]. Chronic exposure to low levels of BPA may still cause developmental toxicity due to the significant po- tential for bioaccumulation in the human placenta and fetus [61]. For example, human BPA levels in the placenta and amniotic fluid were 5 folds higher at weeks 15 to 18 com- pared to maternal serum [62]. Furthermore, fetal and perina- tal exposure to BPA has been linked to several neurodevel- opmental changes and disorders including autism and the related autism spectrum of disorders (ASD), schizophrenia, impaired neurotransmission, attention deficit and hyperactiv- ity disorders, and potentially sexual dimorphic related changes in brain structure and function, as recently reviewed by Brown [51].

Phthalates are a ubiquitous class of environmental terato- gens capable of exerting their toxic effects through several nuclear hormone receptors including the androgen receptor (AR) antagonism [52, 63], ER agonism [52, 64] and/or trans-activation of the peroxisome-proliferator activated receptors (PPAR) and isoforms, either directly or indi- rectly [65-69]. Phthalates are classified as peroxisome prolif- erator chemicals due to their effects on peroxisomal lipid metabolism [70]. Moreover, they may also exert their neuro- toxic effects through altering zinc metabolism [71, 72] or by altering intracellular Ca2+ concentrations leading to the for- mation of reactive oxygen species potentially through a pro- tein kinase C mediated pathway [73]. It has also been sug- gested that DEHP inhibits membrane Na+-K+ ATPase in the rat brain, a phenomena linked to several neurodegenerative and psychiatric disorders [74].

Phthalate reproductive toxicology research [63, 65-69] has been largely focused on di-(2-ethylhexyl)-phthalate



Endocrine Disruptors and Human Health Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 9 849

(DEHP), an industrial plasticizer that is ubiquitously dis- persed in the environment. Human DEHP exposure most likely begins in the mother’s womb, where DEHP has been demonstrated to readily cross the placenta and accumulate in the fetus [67, 68]. DEHP mediated direct or indirect PPAR effects on placental essential fatty acid (EFA) homeostasis have also been of interest [64-69]. The fetus requires mater- nal dietary intake and placental transfer of EFAs to guide proper pregnancy outcomes and fetal development, e.g. neu- rodevelopment [75-78]. The placenta plays a fetoprotective role by accumulating EFAs from maternal circulation and directionally transporting them into fetal compartment [79, 80]. With regards to proper neurodevelopment, EFAs includ- ing docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) are known to play critical roles in mye- logenesis and serve as essential components in neurogenesis, thus making the fetoprotective role of the placenta essential for neurodevelopment [76-80]. EFA imbalances have been linked to several neurological disorders including autism and ASDs, bipolar disorder, and schizophrenia, suggesting that a proper EFA supply is required to protect the CNS develop- ment [81, 82].

PPAR and regulate the expression of several fatty acid transport conferring proteins and metabolizing enzymes that maintain essential fatty acid (EFA) homeostasis and can be trans-activated by DEHP and its metabolites, mono-(2- ethylhexyl)-phthalate (MEHP) and 2-ethylhexanoic acid (EHA) [65, 66, 83]. Recent studies revealed that DEHP and its metabolites MEHP and EHA, can significantly increase the expression of EFA homeostasis proteins, EFA and lipid accumulation in the lipid metabolome of HRP-1 in vitro rat placental cell line [65, 84]. It was also demonstrated that the resulting increase in the expression of fatty acid transport- conferring proteins in these cells also led to a significant increase in fatty acid and lipid accumulation in the cells [85]. DEHP exposure has been revealed to alter the expression of EFA homeostasis proteins in the in vivo rat placenta [66]. In this study, radiolabeled AA and DHA where administered to rat dams at gestational day (GD) 20 and the maternal, pla- cental and fetal disposition of the labeled EFAs were as- sessed [66]. AA was significantly reduced in the maternal and fetal plasma, yet increased significantly in the placenta upon DEHP exposure. DHA levels significantly increased in the maternal plasma and decreased in the fetal plasma upon DEHP exposure contrasted to the control vehicle. DEHP exposure also elicited a statistically significant decrease of both AA and DHA in the developing fetal brain. Lipomic analysis also revealed that DEHP reduced fetal pup brain accumulation of several critical fatty acid and lipid classes including a significant decrease in sphingomyelin (SM) of 54% [69]. DEHP exposure elicited a significant reduction of DHA in five lipid fractions (namely, cholesterol ester (CE), diacylglyceride, phosphatidylserine, lysophasphatidyl cho- line (LYPC) and SM), whereas AA was significantly de- creased CE and LYPC. SM and DHA levels are critical for proper brain development including neurogenesis and neu- ronal differentiation [76-78]. Moreover, the brain weight and active neuronogenesis rapidly increases from GD15 to term in the rat fetus [79]. These results suggest that DEHP may adversely affect on fetal neurodevelopment.

Recently, it has been found that 2,3,7,8-tetrachlorodi- benzo-p-dioxin (TCDD) can reduce n-3 and n-6 EFAs in contrast to the control when administered to the cynomolgus macaque at GD15 or 20 and the brains were isolated at GD24-26 [85]. Although the mechanism of action was not defined, improper neural tube closing and other neurodevel- opmental aberrations were observed and attributed to the improper EFA balance [86-89]. Interestingly, TCDD also has an estrogenic response, acting through ERs, potentially interacting with the aryl hydrocarbon receptor (AHR) in rats [90, 91].

In summary, several EDCs have been demonstrated to

exert their teratogenic effects on fetal neurodevelopment.

Considerable attention is necessary to elucidate the mecha-

nisms by which individual or multiple combinations of

EDCs can elicit fetal neurotoxicity. The extent to which the

animal data may be extrapolated to predict a human response

will also need to be determined.



Normal human sex differentiation, growth and puberty

are critically dependent upon hormonal actions, opening up

for targeting by EDCs. Recent epidemiological studies dem-

onstrate increasing incidences of related developmental dis-

orders in children originating in embryonic and fetal life

[92]. Environmental influences may play an important role

in the pathogenesis of such disorders although the factors

involved remain to be characterized [7,8].

Disorders of Sex Development (DSD)

It has been hypothesized that certain defined disorders of male sex differentiation may be linked by common patho- genic mechanisms [92]. Cryptorchidism, hypospadia, testicu- lar cancer and poor semen quality are all proposed to be components of this “syndrome”. It has been suggested that exposure to environmental estrogens or anti-androgens may alter the fetal hormonal balance, or compete directly with the androgen receptor, causing undermasculinization of male fetuses. A severe outcome of such action would potentially result in DSD with an intersex phenotype at birth. Less se- vere disruption may cause maldescended testes or hypo- spadia. More recently, epigenetic alterations with transgen- erational influences have been implicated in the effects of EDCs on reproductive functions [93].


Cryptorchidism is difficult to study due to poor reporting

but certain investigations point to an increased incidence in

some countries during several decades [94]. Model sub-

stances, particularly antiandrogens, have been associated

with cryptorchidism in experimental animals [94]. Prenatal

exposure to pesticides (as indicated from concentrations in

breast milk) has been linked with an increased risk of cryp-

torchidism [95]. Higher organochlorine concentrations were

found in fat samples from cryptorchid boys when compared

with control samples [96] but other studies have failed to

demonstrate similar correlations [97]. Although data is ac-

cumulating, at the present time no single EDC can be con-

vincingly blamed for causing cryptorchidism.



850 Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 9 Latini et al.


Hypospadia is underreported to malformation registries, mainly since the most common mild cases are not reported. Still there are reports from reliable sources indicating an increased incidence in European countries. Large regional variation seems to exist [98, 99]. Similarly to cryp- torchidism, exposure studies investigating links to EDCs have come to opposing results and it is fair to say that at the present stage of knowledge the data are inconclusive, mainly due to low power and poor disease classification of most published studies.


The onset and tempo of puberty are under endocrine con- trol and there is evidence to indicate that EDCs may affect pubertal development [100]. The proposed adverse effects of EDCs are most often related to premature thelarche in girls. Studies in the US have demonstrated a recent trend to an earlier start of puberty in girls, particularly in certain ethnic groups, with a direct correlation to obesity, as assessed as Body Mass Index (BMI). Exposure to EDCs has been pro- posed to play a role in this novel trend [101]. One group re- cently found a similar development in Denmark but failed to show a correlation with BMI and levels of reproductive hormones [102]. This indicates an influence by environ- mental factors, the natures of which are yet to be determined.


EDCs may exert unwanted actions on thyroid function [103]. Links between exposure to PCBs and increased thy- roid stimulating hormone have been observed by some [104, 105], but not other authors [106 107]. PCB has been pro- posed to exert goiterogenic actions [108], and pentachloro- phenol indicated to suppress thyroid hormone levels in new- borns [109]. Given the critical role of the thyroid for fetal and infant neurodevelopment, such action may be associated with adverse neurodevelopmental consequences in children.


EDCs are known to exert harmful actions in the adrenal cortex. DDT metabolites are well known inhibitors of adre- nal function [110], exerting direct cytotoxicity to adrenocor- tical cells. Certain EDCs may have a negative impact on adrenal steroidogenesis. The phytoestrogen resveratrol was found to suppress glucocorticoid production by inhibiting 21-hydroxylase [5]. This may impair glucocorticoid driven stress responses, which is a crucial component of the host- defense system against infection and injury.



Autoimmune endocrine disorders are diseases of the en- docrine glands caused by an impaired response of the im- mune system, which fails to recognize self-antigens and re- acts against them [111]. Most autoimmune endocrine disor- ders target single organs, but often patients have multiple autoimmune endocrine disorders or autoimmune polyglandu- lar syndromes, where, two or more endocrine glands are in- volved by the autoimmune process [112]. Autoimmune en- docrine disorders include: type 1 diabetes mellitus, Hashi-

moto’s thyroiditis, Graves’ disease, Addison’s disease, auto- immune hypophysitis, autoimmune oophritis, autoimmune hypoparathyroidism, testicular insufficiency, and premature ovarian failure.

Autoimmune diseases are usually the result of an inter- play between genetic and acquired factors; the latter includ- ing also environmental influences [112]. Autoimmune endo- crine diseases often present a sexual dimorphism, which suggests a potential role of sexual hormones on the immune system and therefore their contribution to autoimmune dis- orders [113].

Several studies have reported that sex steroid hormones can modulate the immune system [114]. Although, it is im- portant to bear in mind that the response to sex hormones can vary among individuals, in relation to age, genetic back- ground, duration and level of exposure; in general estrogens and androgens appear to have opposite effects on the im- mune system [115]. In particular, estrogen treatment in mice has been associated with reduced number of lymphocytes in several organs as well as with a deregulation in the balance between T and B lymphocytes [115]. The most common finding has been an estrogen-related induction of B-cell hy- peractivity and T-cell hypoactivity [115]. This enhanced immunoreactivity in females has been defined as a ‘double- edged sword’, which on the one hand protects against infec- tions, whereas on the other hand increases the risk of developing autoimmune diseases [116].

There is growing evidence suggesting that EDCs can affect the immune system, promoting the development of autoimmune diseases [117]. An example is given by envi- ronmental estrogens, which could exert the same effect than endogenous estrogens on the immune system [113]. EDCs could act on the immune system through different mecha- nisms [118]: 1) inhibiting the processes involved in estab- lishing tolerance, with generation of autoreactive cells; 2) modifying gene expression in cells involved in the immune response, permitting lymphocytes to respond to signals nor- mally insufficient to initiate a response or permitting the antigen-presenting cells to abnormally stimulate a response; 3) modifying self-molecules such that they are recognized by the immune system as foreign.

Yurino et al. [119] have demonstrated that EDCs, such as diethylstilbestrol and bisphenol-A (BPA), can stimulate autoantibody production

by B1 cells both in vitro and in

vivo. The majority of data related to ED and autoimmunity are on animal models of lupus [114]. It has been shown that prolactin or estrogen levels accelerate disease activity in lu- pus-prone mice or can induce a lupus-like syndrome in nor- mal mice. Scant data are available on the effect of ED spe- cifically on endocrine autoimmune diseases [120] and there- fore, this area needs further explorations.



Over the years the need for risk assessments has in- creased because of the potential health risks related to expo- sure to EDs in everyday life worldwide. Biological monitor- ing, defined as measuring concentrations of chemicals and



Endocrine Disruptors and Human Health Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 9 851

their metabolites in human body fluids, has been shown to represent an accurate, efficient and cost-effective exposure assessment to environmental pollutants even at low levels [121]. By detecting non-invasive biomarkers through appro- priate analytical procedures, human bio-monitoring (HBM) takes into account all routes and sources of exposure, thus representing an ideal instrument for risk assessment and risk management [122, 123]. The sensitivity of HBM methods enables the elucidation of the metabolism and modes of ac- tion of pollutants in humans. The diesters of benzene-1,2- dicarboxylic (phthalic) acid, commonly known as phthalates, are a family of industrial compounds with a common chemi- cal structure, dialkyl or alkyl/aryl esters of 1,2- benzenedicarboxylic acid [124]. They are high-production- volume synthetic chemicals and the probability of exposure to these chemicals is high because of their use in plastic items and other common consumer products, including per- sonal-care products (e.g., perfumes, lotions, cosmetics), paint, industrial plastics, medical devices and pharmaceuti- cals; phthalates are primarily used as plasticizers to impart flexibility to an otherwise rigid polyvinylchloride (PVC) [124]. As these plasticizers are not chemically bound to PVC, they elute at a constant rate from plastic products into the environment. Phthalates have been found everywhere, even in infant formulas and breast milk [125, 126].

Recently, food has been observed to be the predominant intake source of DEHP, whilst other sources, such as enteric coatings in medications, considerably contributed to the daily intake of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) in an adult population [127, 128]. A com- parison of the available data resulting from the determination of the target compound in indoor air and house dust as well as emission studies with the results from the HBM studies reveals that only a small portion of intake takes place via the air, dust paths and personal care products, such as cosmetics [129, 130].

Phthalates are rapidly metabolized to their monoesters, which can be further transformed into oxidative metabolites, conjugated, and both free and conjugated metabolites ex- creted in the urine and faeces [131].

Due to their chemical properties exposure to phthalates does not result in bioaccumulation [132].

Urinary secondary metabolites have been shown to repre- sent ideal biomarkers of exposure to phthalates, allowing accurate assessments of human exposure from multiple sources and routes; the use of metabolites also avoids the analytical problems caused by the risk of sample’s contami- nation by the ubiquitous parent phthalates [133-135].

As there may be significant demographic variations in exposure and/or metabolism of phthalates, health-risk as- sessments for phthalate exposure in humans should consider different potential risk groups [136].

During the last decades, a great deal of scientific and public concern has been raised about the potential health hazards posed by exposures to phthalates, even in environ- mental concentrations [137-144].

In particular, phthalates with side-chain lengths C4 to C6 are known to adversely affect the differentiation and function of the reproductive system [145-149].

The Center for the Evaluation of Risks to Human Repro- duction (CERHR) identified two specific situations as poten- tially problematic, the exposure of young children to di- isononyl phthalate (DINP) through the use of toys or to DEHP from medical devices [150].

To this regard, exposure assessment have observed that the exposure of children to phthalates exceeds that in adults and the tolerable intake of children is frequently exceeded, in some instances up to 20-fold [151,152].

On the other hand, newborns in the Neonatal Intensive Care Unit (NICU) environment represent a population at particularly increased risk for exposure to DEHP, because of their physical conditions, small body size and contemporary exposure to multiple medical devices containing DEHP. To this regard, it has been documented that these newborns can be exposed up to 100 times above the limit values, depend- ing on the intensity of medical care [153, 154]. As a conse- quence, the U.S.A and European Union promulgated limita- tions of use for certain phthalates [155]. Although several risk assessments have been finalized for these chemicals during the last decade, in the future there is the need for risk assessments able to cover a high number of exposure situa- tions and a transparent process of collecting data, thus ensur- ing the safety of workers and consumers [156].


There is accumulating evidence suggesting that EDCs represent a large and heterogeneous group of chemical com- pounds that may potentially affect human health, especially if exposures occur at early stages in life, including both pre- natal life and early childhood. Effects are especially relevant in relation to the long-term development of the reproductive and nervous systems, as well as for metabolic programming.

Factors co-modulating the risk, besides age and gender, include diet and lifestyle.

As a consequence, in the future risk assessment of human health should include: (i) population-based estimates of envi- ronmental total exposure levels from several sources using HBM; (ii) further studies to assess interactions between sev- eral different classes of ubiquitous compounds and their combined effect; iii) characterization of appropriate bio- markers of effective dose and susceptibility for major groups of EDCs.


Part of the work has been performed within the frame of the activities of the Network of Excellence CASCADE (6th framework programme, <http://www.>).

The authors gratefully acknowledge the support of Mrs. Francesca Baldi (Istituto Superiore di Sanità – Roma, Italy) in the preparation of the manuscript.


[1] Caserta, D.; Maranghi, L.; Mantovani, A.; Marci, R.; Maranghi, F.; Moscarini, M. Impact of endocrine disruptor chemicals in gynae-

cology. Hum. Reprod. Updat. 2008, 14, 59-72.



852 Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 9 Latini et al.

[2] Landrigan, P.; Garg, A.; Droller, DB. Assessing the effects of en-

docrine disruptors in the National Children’s Study. Environ. Health Perspect., 2003, 111, 1678-1682.

[3] Svechnikov, K.; Svechnikova, I.; Söder, O. Inhibitory effects of mono-ethylhexyl phthalate on steroidogenesis in immature and

adult rat Leydig cells in vitro. Reprod. Toxicol., 2008, 25, 485-490. [4] Svechnikova, I.; Svechnikov, K.; Söder, O. The influence of di-(2-

ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats. J. Endocrinol., 2007, 194, 603-609.

[5] Supornsilchai, V.; Svechnikov, K.; Seidlova-Wuttke, D.; Wuttke, W.; Söder, O. Phytoestrogen resveratrol suppresses steroidogenesis

by rat adrenocortical cells by inhibiting cytochrome P450 c21- hydroxylase. Horm. Res., 2005, 64, 280-286.

[6] Latini, G.; Scoditti, E.; Verrotti, A.; De Felice, C.; Massaro, M. Peroxisome proliferator-activated receptors as mediators of phtha-

late-induced effects in the male and female reproductive tract: epi- demiological and experimental evidence. PPAR. Res., 2008, 2008,

359-367. [7] Pombo, M.; Castro-Feijóo, L. Endocrine disruptors. J. Pediatr.

Endocrinol. Metab., 2005, 18(Suppl 1), 1145-1155. [8] Waring, R.H.; Harris, R.M. Endocrine disrupters: a human risk?

Mol. Cell. Endocrinol., 2005, 244, 2-9. [9] Whitehead, S.A.; Rice, S. Endocrine-disrupting chemicals as

modulators of sex steroid synthesis. Best Pract. Res. Clin. Endocri- nol. Metab., 2006, 20, 45-61.

[10] Henley, D.V.; Korach, K.S. Endocrine-disrupting chemicals use distinct mechanisms of action to modulate endocrine system func-

tion. Endocrinology., 2006, 147(Suppl 6), 25-32. [11] Iguchi, T.; Watanabe, H.; Katsu, Y. Application of ecotoxicoge-

nomics for studying endocrine disruption in vertebrates and inver- tebrates. Environ. Health Perspect., 2006, 114(Suppl 1), 101-105.

[12] Schulte-Oehlmann, U.; Albanis, T.; Allera, A.; Bachmann, J.; Berntsson, P.; Beresford, N.; Carnevali, D.C.; Ciceri, F.; Dagnac,

T.; Falandysz, J.; Galassi, S.; Hala, D.; Janer, G.; Jeannot, R.; Job- ling, S.; King, I.; Klingmüller, D.; Kloas, W.; Kusk, K.O.; Levada,

R.; Lo, S.; Lutz, I.; Oehlmann, J.; Oredsson, S.; Porte, C.; Rand- Weaver, M.; Sakkas, V.: Sugni, M.; Tyler, C.; van Aerle, R.; van

Ballegoy, C.; Wollenberger, L. Comprendo: Focus and approach. Environ. Health Perspect., 2006, 114(Suppl 1), 98-100.

[13] Gore, A.C. Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems. Front. Neuroen-

docrinol., 2008, 29, 358-374. [14] Crews, D.; Gore, A.C.; Hsu, T.S.; Dangleben, N.L.; Spinetta, M.:

Schallert, T.; Anway, M.D.; Skinner, M.K. Transgenerational epi- genetic imprints on mate preference Proc. Natl. Acad. Sci. U S A.,

2007, 104, 5942-5946. [15] Hokanson, R.; Hanneman, W.; Hennessey, M:; Donnelly, K.C.;

McDonald, T.; Chowdhary, R.; Busbee, D.L. DEHP, bis(2)- ethylhexyl phthalate, alters gene expression in human cells: possi-

ble correlation with initiation of fetal developmental abnormalities. Hum. Exp. Toxicol., 2006, 25, 687-695.

[16] Willingham.; E. Endocrine-disrupting compounds and mixtures: unexpected dose-response. Arch. Environ. Contam. Toxicol., 2004,

46, 265-269. [17] Fromme, H.; Albrecht, M.; Angerer, J.; Drexler, H.; Gruber, L.;

Schlummer, M.; Parlar, H.; Korner, W.; Wanner, A.; Heitmann, D.; Roscher, E.; Bolte, G. Integrated Exposure Assessment Survey

(INES) exposure to persistent and bioaccumulative chemicals in Bavaria, Germany. Int. J. Hyg. Environ. Health., 2007, 210, 345-

349. [18] European Food Safety Authority. Opinion of the Scientific Panel

on Contaminants in the Food Chain on a request from the Commis- sion to assess the health risks to consumers associated with expo-

sure to organotins in foodstuffs. EFSA J., 2004, 102, 1-119. [19] Baldi, F.; Mantovani, A. A new database for food safety: EDID

(Endocrine disrupting chemicals – Diet Interaction Database). Ann. Ist. Super. Sanità., 2008, 44, 57-63.

[20] Fattore, E.; Fanelli, R.; Turrini, A.; Di Domenico, A. Current dietary exposure to polychlorodibenzo-p-dioxins.; poly-

chlorodibenzofurans and dioxin-like polychlorobiphenyls in Italy. Mol. Nutr. Food. Res., 2006, 50, 915-921.

[21] Mozaffarian, D.; Rimm, E.B. Fish intake, contaminants and human health: evaluating the risks and the benefits. JAMA, 2006, 296,


[22] European Food Safety Authority. Opinion of the Scientific Panel

on Contaminants in the food chain on a request from the European Parliament related to the safety assessment of wild and farmed fish.

EFSA J., 2005, 236, 1-118. [23] Martin, J.H.; Crotty, S.; Nelson, P.N. Phytoestrogens: perpetrators

or protectors? Future Oncol., 2007, 3, 307-318. [24] European Food Safety Authority. Opinion of the Scientific Panel

on Additives and Products or Substances used in Animal Feed on the request from the Commission on the use of iodine in

feedigstuffs. EFSA J., 2005,168, 1-42. [25] De Angelis, S.; Tassinari,R.; Maranghi, F.; Eusepi, A.; Di Virgilio,

A.; Chiarotti, F.; Ricceri, L.; Venerosi Pesciolini, A.; Gilardi, E.; Moracci, G.; Calamandrei, G.; Olivieri, A.; Mantovani, A. Devel-

opmental exposure to chlorpyrifos induces alterations in thyroid and thyroid hormone levels without other toxicity signs in cd1

mice. Toxicol. Sci., 2009, 108, 311-319. [26] Wenzel, A.; Franz, C.; Breous, E.; Loos, U. Modulation of iodide

uptake by dialkyl phthalate plasticisers in FRTL-5 rat thyroid fol- licular cells. Mol. Cell. Endocrinol., 2005, 244, 63-71.

[27] Divi, R.L.; Doerge, D.R. Inhibition of thyroid peroxidase by die- tary flavonoids. Chem. Res. Toxicol., 1996, 9, 16-23.

[28] Milerová, J.; Cerovská, J.; Zamrazil, V.; Bílek, R.; Lapcík ,O.; Hampl, R. Actual levels of soy phytoestrogens in children correlate

with thyroid laboratory parameters. Clin. Chem. Lab. Med., 2006, 44, 171-174.

[29] Paulus, B.F.; Bazar, M.A.; Salice, C.J.; Mattie, D.R.; Major, M.A. Perchlorate inhibition of iodide uptake in normal and iodine-

deficient rats. J. Toxicol. Environ. Health A., 2007, 70, 1142-1149. [30] Saarinen, N.M.; Bingham, C.; Lorenzetti, S.; Mortensen, A.A.;

Mäkela, S.; Penttinen, P.; Sorensen, I.K.; Valsta, L.M.; Virgili, F.; Vollmer, G.; Wärri, A.; Zierau, O. Tools to evaluate estrogenic po-

tency of dietary phytoestrogens: a consensus paper from the EU thematic network “Phytohealth” (QLKI-2002-2453). Genes Nutr.,

2006, 1, 143-158. [31] Peeters, P.H.; Slimani, N.; van der Schouw, Y.T.; Grace, P.B.;

Navarro, C.; Tjonneland, A.; Olsen, A.; Clavel-Chapelon, F.; Touillaud, M.; Boutron-Ruault, M.C.; Jenab, M.; Kaaks, R.; Lin-

seisen, J.; Trichopoulou, A.; Trichopoulos, D.; Dilis, V.; Boeing, H.; Weikert, C.; Overvad, K.; Pala, V.; Palli, D.; Panico, S.; Tu-

mino, R.; Vineis, P.; Bueno-de-Mesquita, H.B.; van Gils, C.H.; Skeie, G.; Jakszyn, P.; Hallmans, G.; Berglund, G.; Key, T.J.;

Travis, R.; Riboli, E.; Bingham, S.A. Variations in plasma phytoes- trogen concentrations in European adults. J. Nutr., 2007,137, 1294-

300. [32] Han, D.H.; Denison, M.S.; Tachibana, H.; Yamada, K. Relation-

ship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids. Biosci.

Biotechnol. Biochem., 2002, 66, 1479-1487. [33] Rajapakse, N.; Silva, E.; Scholze, M.; Kortenkamp, A. Deviation

from additivity with estrogenic mixtures containing 4-nonylphenol and 4-tert-octylphenol detected in the E-SCREEN assay. Environ.

Sci. Technol., 2004, 38, 6343-6352. [34] Madia, F.; Giordano, G.; Fattori, V.; Vitalone, A.; Branchi, I.;

Capone, F.; Costa, L.G. Differential in vitro neurotoxicity of the flame retardant PBDE-99 and of the PCB Aroclor 1254 in human

astrocytoma cells. Toxicol. Lett., 2004, 154, 11-21. [35] Guo, T.L.; Zhang, X.L.; Bartolucci, E.; McCay, J.A.; White, K.L

Jr.; You, L. Genistein and methoxychlor modulate the activity of natural killer cells and the expression of phenotypic markers by

thymocytes and splenocytes in F0 and F1 generations of Sprague- Dawley rats. Toxicology, 2002, 172, 205-215.

[36] Penza, M.; Montani, C.; Romani, A.; Vignolini, P.; Ciana, P.; Maggi, A.; Pampaloni, B.; Caimi, L.; Di Lorenzo, D. Genistein ac-

cumulates in body depots and is mobilized during fasting.; reaching estrogenic levels in serum that counter the hormonal actions of es-

tradiol andorganochlorines. Toxicol. Sci ., 2007, 97, 299-307. [37] van Meeuwen, J.A.; van den Berg, M.; Sanderson, J.T.; Verhoef,

A.; Piersma, A.H. Estrogenic effects of mixtures of phyto- and syn- thetic chemicals on uterine growth of prepubertal rats. Toxicol.

Lett., 2007, 170, 165-176. [38] Vilela, M.L.; Willingham, E.; Buckley, J.; Liu, B.C.; Agras, K.;

Shiroyanagi, Y.; Baskin L.S. Endocrine disruptors and hypo- spadias: role of genistein and the fungicide vinclozolin. Urology,

2007, 70, 618-621.



Endocrine Disruptors and Human Health Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 9 853

[39] Dolinoy, D.C.; Huang, D.; Jirtle, R.L. Maternal nutrient supple-

mentation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc. Natl. Acad. Sci. USA, 2007, 104,

13056-13061. [40] Murphy, K.A.; Quadro, L.; White, L.A. The intersection between

the aryl hydrocarbon receptor (AhR) and retinoic acid-signaling pathways. Vitam. Horm., 2007, 75, 33-67.

[41] Yang, Y.M.; Huang, D.Y.; Liu, G.F.; Zhong, J.C.; Du, K.; Li, Y.F.; Song, X.H. Inhibitory effects of vitamin A on TCDD-induced cyto-

chrome P-450 1A1 enzyme activity and expression. Toxicol. Sci., 2005, 85, 727-734.

[42] Hoegberg, P.; Schmidt,C.K.; Fletcher, N.; Nilsson, C.B.; Trossvik, C.; Gerlienke Schuur, A.; Brouwer, A.; Nau, H.; Ghyselinck,N.B.;

Chambon, P.; Hakansson, H. Retinoid status and responsiveness to 2.;3.;7.;8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking

retinoid binding protein or retinoid receptor forms. Chem. Biol. In- teract., 2005, 156, 25-39.

[43] Fletcher, N.; Giese, N.; Schmidt, C.; Stern, N.; Lind, P.M.; Viluk- sela, M.; Tuomisto, J.T.; Tuomisto, J.; Nau, H.; Hakansson, H. Al-

tered retinoid metabolism in female Long-Evans and Han/Wistar rats following long-term 2.;3.;7.;8-tetrachlorodibenzo-p-dioxin

(TCDD)-treatment. Toxicol. Sci., 2005, 86, 264-272. [44] Nishimura, N.; Yonemoto, J.; Miyabara, Y.; Fujii-Kuriyama, Y.;

Tohyama, C. Altered thyroxin and retinoid metabolic response to 2.;3.;7.;8-tetrachlorodibenzo-p-dioxin in aryl hydrocarbon receptor-

null mice. Arch. Toxicol., 2005 ,79, 260-267. [45] van der Ven, L.T.; van de Kuil, T.; Verhoef, A.; Leonards, P.E.;

Slob, W.; Cantón, R.F.; Germer, S.; Hamers, T.; Visser, T.J.; Lit- ens, S.; Hakansson, H.; Fery, Y.; Schrenk, D.; van den Berg, M.;

Piersma, A.H.; Vos, J.G. A 28-day oral dose toxicity study en- hanced to detect endocrine effects of a purified technical pentab-

romodiphenyl ether (pentaBDE) mixture in Wistar rats. Toxicology, 2008, 245, 109-122.

[46] Zhou, C.; Zhang C. Protective effects of antioxidant vitamins on Aroclor 1254-induced toxicity in cultured chicken embryo hepato-

cytes. Toxicol. In vitro, 2005, 19, 665-673. [47] Birnbaum, L. S. Developmental effects of dioxins and related en-

docrine disrupting chemicals. Toxicol. Lett., 1995, 82-83, 743-750. [48] Palanza, P.; Gioiosa, L.; vom Saal, F. S.; Parmigiani, S. Effects of

developmental exposure to bisphenol A on brain and behavior in mice. Environ. Res., 2008, 108, 150-157.

[49] Le, H. H.; Carlson, E. M.; Chua, J. P.; Belcher, S. M. Bisphenol A is released from polycarbonate drinking bottles and mimics the

neurotoxic actions of estrogen in developing cerebellar neurons. Toxicol. Lett., 2008, 176, 149-156.

[50] Nakamura, K.; Itoh, K.; Sugimoto, T.; Fushiki, S. Prenatal expo- sure to bisphenol A affects adult murine neocortical structure. Neu-

rosci. Lett., 2007, 420, 100-105. [51] Brown Jr., J. S. Effects of Bisphenol-A and Other Endocrine Dis-

ruptors Compared With Abnormalities of Schizophrenia: An Endo- crine-Disruption Theory of Schizophrenia. Schizophr. Bull., 2009,

35, 256-278. [52] Yang, M; Park, M. S.; Lee, H. S. Endocrine disrupting chemicals:

human exposure and health risks. J. Environ. Sci. Health, Part C., 2006, 24, 183-224.

[53] Kortenkamp, A. Ten years of mixing cocktails: a review of combi- nation effects of endocrine-disrupting chemicals. Environ. Health

Perspect., 2007, 115(Suppl 1), 98-105. [54] Coles, L. S.; Eddington, N. D. AAPS Newsmagazine, 2007, 10, 18.

[55] Hans, M.; Ursula, G.-R. Bisphenol A levels in blood depend on age and exposure. Toxicol. Lett., 2009, [Epub June 26, 2009].

[56] Takayanagi, S.; Tokunaga, T.; Liu, X.; Okada, H.; Matsushima, A.; Shimohigashi, Y. Endocrine disruptor bisphenol A strongly binds

to human estrogen-related receptor gamma (ERRgamma) with high constitutive activity. Toxicol. Lett., 2006, 167, 95-105.

[57] Kimura-Kuroda, J.; Nagata, I.; Kuroda, Y. Disrupting effects of hydroxy-polychlorinated biphenyl (PCB) congeners on neuronal

development of cerebellar Purkinje cells: a possible causal factor for developmental brain disorders? Chemosphere, 2007, 67, S412-

420. [58] Völkel, W.; Colnot, T.; Csanády, G. A.; Filser, J. G.; Dekant, W.

Metabolism and kinetics of bisphenol a in humans at low doses fol- lowing oral administration. Chem. Res. Toxicol., 2002, 15, 1281-


[59] Calafat, A. M.; Kuklenyik, Z.; Reidy, J. A.; Caudill, S. P.; Ekong,

J.; Needham, L. L. Urinary concentrations of bisphenol A and 4- nonylphenol in a human reference population. Environ. Health

Perspect., 2005, 113, 391-395. [60] Stahlhut, R. W.; Welshons, W. V.; Swan, S. H. Bisphenol A data in

NHANES suggest longer than expected half-life, substantial non- food exposure, or both. Environ. Health Perspect., 2009, 117, 784-

789. [61] Schönfelder, G.; Wittfoht, W.; Hopp, H.; Talsness, C. E.; Paul, M.;

Chahoud, I. Parent bisphenol A accumulation in the human mater- nal-fetal-placental unit. Environ. Health Perspect., 2002, 110,

A703-707. [62] Zoeller, R. T.; Bansal, R.; Parris, C. Bisphenol-A, an environ-

mental contaminant that acts as a thyroid hormone receptor antago- nist in vitro, increases serum thyroxine, and alters RC3/neurogranin

expression in the developing rat brain. Endocrinology, 2005, 146, 607-612.

[63] Kavlock, R.; Boekelheide, K.; Chapin, R.; Cunningham, M.; Faustman, E.; Foster, P.; Golub, M.; Henderson, R.; Hinberg, I.;

Little, R.; Seed, J.; Shea, K.; Tabacova, S.; Ty, R.; Williams, P.; Zacharewski, T. NTP Center for the Evaluation of Risks to Human

Reproduction: phthalates expert panel report on the reproductive and developmental toxicity of di(2-ethylhexyl) phthalate. Reprod.

Toxicol., 2002, 16, 529-653. [64] Lu, K. Y.; Tseng, F. W.; Wu, C. J.; Liu, P. S. Suppression by

phthalates of the calcium signaling of human nicotinic acetylcho- line receptors in human neuroblastoma SH-SY5Y cells.Toxicology,

2004, 200, 113. [65] Xu, Y.; Cook, T. J.; Knipp, G. T. Effects of di-(2-ethylhexyl)-

phthalate (DEHP) and its metabolites on fatty acid homeostasis regulating proteins in rat placental HRP-1 trophoblast cells. Toxi-

col. Sci., 2005, 84, 287-300. [66] Xu, Y.; Agarwal, S.; Cook, T. J.; Knipp, G. T. Maternal di-(2-

ethylhexyl)-phthalate exposure influences essential fatty acid ho- meostasis in rat placenta. Placenta, 2008, 29, 962-969.

[67] Latini, G.; Del Vecchio, A.; Massaro, M.; Verotti, A.; De Felice, C. In utero exposure to phthalates and fetal development. Curr. Med.

Chem., 2006, 13, 2527-2534. [68] Latini, G.; De Felice, C.; Presta, G.; Del Vecchio, A.; Paris, I.;

Ruggieri, F.; Mazzeo, P. Status epilepticus and neurodevelopmen- tal outcome at 2 years of age in an extremely low birth weight in-

fant. Biol. Neonate, 2003, 83, 22-24. [69] Xu, Y.; Agarwal, S.; Cook, T. J.; Knipp, G. T. Di-(2-ethylhexyl)-

phthalate affects lipid profiling in fetal rat brain upon maternal ex- posure. Arch. Toxicol., 2007, 81, 57-62.

[70] Cimini, A.; Sulli, A.; Stefanini, S.; Serafini, B.; Moreno, S.; Rossi, L.; Giorgi, M.; Ceru, M. P. Effects of Di-(2-ethylhexyl)phthalate

on peroxisomes of liver, kidney and brain of lactating rats and their pups. Cell Mol. Biol., 1994, 40, 1063-1076.

[71] Peters, J. M.; Taubeneck, M. W.; Keen, C. L.; Gonzalez, F. J. Di(2- ethylhexyl) phthalate induces a functional zinc deficiency during

pregnancy and teratogenesis that is independent of peroxisome pro- liferator-activated receptor-alpha. Teratology, 1997, 56, 311-316.

[72] Johnson, S. Micronutrient accumulation and depletion in schizo- phrenia, epilepsy, autism and Parkinson’s disease? Med. Hypothe-

ses, 2001, 56, 641-645. [73] Palleschi, S.; Rossi, B.; Diana, L.; Silvestroni, L. Di(2-

ethylhexyl)phthalate stimulates Ca(2+) entry, chemotaxis and ROS production in human granulocytes. Toxicol. Lett., 2009, 187, 52-57.

[74] Dhanya, C. R.; Indu, A. R.; Deepadevi, K. V.; Kurup, P. A. Inhibi- tion of membrane Na(+)-K+ Atpase of the brain, liver and RBC in

rats administered di(2-ethyl hexyl) phthalate (DEHP) a plasticizer used in polyvinyl chloride (PVC) blood storage bags. Indian J.

Exp. Biol., 2003, 41, 814-820. [75] Latini, G. Potential hazards of exposure to di-(2-ethylhexyl)-

phthalate in babies. a review. Biol. Neonate, 2000, 78, 269-276. [76] Jumpsen, J.; Clandinin, M. T. Brain Development: Relationship to

Dietary Lipid and Lipid Metabolism. AOCS Press, Champaign, IL, 1995.

[77] Wainright, P. E. Dietary essential fatty acids and brain function: a developmental perspective on mechanisms. Proc. Nutr. Soc., 2002,

61, 61-69. [78] Uauy, R.; Dangour, A.D. Nutrition in brain development and aging:

role of essential fatty acids. Nutr. Rev., 2006, 64, S24-33.



854 Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 9 Latini et al.

[79] Haggarty, P. Placental regulation of fatty acid delivery and its

effect on fetal growth–a review. Placenta, 2002, 23, S28-38. [80] Haggarty, P. Effect of placental function on fatty acid requirements

during pregnancy. Eur. J. Clin. Nutr., 2004, 58, 1559-1570. [81] Vancassel, S.; Durand, G.; C Barthelemy, C.; Lejeune, B.; Marti-

neau, J.; Guilloteau, D.; Andres, C.; Chalon, S. Plasma fatty acid levels in autistic children. Prostaglandins Leukot. Essent. Fatty Ac-

ids, 2001, 65, 1-7. [82] Richardson, A. J.; Ross, M. A. Fatty acid metabolism in neurode-

velopmental disorder: a new perspective on associations between attention-deficit/hyperactivity disorder, dyslexia, dyspraxia and the

autistic spectrum. Prostaglandins Leukot. Essent. Fatty Acids, 2000, 63, 1-9.

[83] Maloney, E. K.; Waxman, D. J. trans-Activation of PPARalpha and PPARgamma by structurally diverse environmental chemicals.

Toxicol. Appl. Pharmacol., 1999, 161, 209-218. [84] Xu, Y.; Knipp, G. T.; Cook, T. J. Effects of di-(2-ethylhexyl)-

phthalate and its metabolites on the lipid profiling in rat HRP-1 trophoblast cells. Arch. Toxicol. Sci., 2006, 80, 293-298.

[85] Moran, F. M.; Hendrickx, A. G.; Shideler, S.; Overstreet, J.W.; Watkins, S. M.; Lasley, B. L. Effects of 2,3,7,8-tetrachlorodibenzo-

p-dioxin (TCDD) on fatty acid availability and neural tube forma- tion in cynomolgus macaque, Macaca fascicularis. Birth Defects

Res. B Dev. Reprod. Toxicol., 2004, 71, 37-46. [86] Shiota, K,; Mima, S. Assessment of the teratogenicity of di(2-

ethylhexyl)phthalate and mono(2-ethylhexyl)phthalate in mice. Arch. Toxicol., 1985, 56, 263-266.

[87] Shea, K. M. Pediatric exposure and potential toxicity of phthalate plasticizers. Pediatrics, 2003, 111, 1467-1474.

[88] Shiota, K.; Nishimura, H., Teratogenicity of di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) in mice. Environ.

Health Perspect., 1982, 45, 65-70. [89] Shiota, K.; Chou, M. J.; Nishimura,H. Embryotoxic effects of di-2-

ethylhexyl phthalate (DEHP) and di-n-buty phthalate (DBP) in mice. Environ. Res., 1980, 22, 245-253.

[90] Tanaka, J.; Yonemoto, J.; Zaha, H.; Kiyama, R.; Sone, H. Estro- gen-responsive genes newly found to be modified by TCDD expo-

sure in human cell lines and mouse systems. Mol. Cell. Endocri- nol., 2007 272, 38-49.

[91] Valdez, K. E.; Shi, Z.; Ting, A. Y.; Petroff, B. K. Effect of chronic exposure to the aryl hydrocarbon receptor agonist 2,3,7,8-

tetrachlorodibenzo-p-dioxin in female rats on ovarian gene expres- sion. Reprod. Toxicol., 2009, 28, 32-37.

[92] Skakkebaek,, N.E. ; Rajpert-De Meyts, E. ; Main, K.M. Testicular dysgenesis syndrome: an increasingly common developmental dis-

order with environmental aspects. Hum. Reprod., 2001, 16, 972- 928.

[93] Anway, M.D.; Cupp, A.S.; Uzumcu, M.; Skinner, M.K. Epigenetic transgenerational actions of endocrine disruptors and male fertility.

Science, 2005, 308, 1466-1469. [94] Main, K.M.; Skakkebaek, N.E.; Toppari, J. Cryptorchidism as part

of the testicular dysgenesis syndrome: the environmental connec- tion. Endocr. Dev., 2009, 14, 167-173.

[95] Damgaard, I.N.; Skakkebaek, N.E.; Toppari, J.; Virtanen, H.E.; Shen, H.; Schramm, K.W.; Petersen, J.H.; Jensen, T.K.; Main,

K.M.; Nordic Cryptorchidism Study Group. Persistent pesticides in human breast milk and cryptorchidism. Environ. Health Perspect.,

2006, 114, 1133-1138. [96] Hosie, S.; Loff, S.; Witt, K.; Niessen, K.; Waag, K.L. Is there a

correlation between organochlorine compounds and undescended testes? Eur. J. Pediatr. Surg., 2000, 10, 304-309.

[97] Langer, P.; Kocan, A.; Tajtáková, M.; Petrík, J.; Chovancová, J.; Drobná, B.; Jursa, S.; Pavúk, M.; Koska, J.; Trnovec, T.; Seböková,

E.; Klimes, I. Possible effects of polychlorinated biphenyls and or- ganochlorinated pesticides on the thyroid after long-term exposure

to heavy environmental pollution. J Occup Environ. Med., 2003, 45, 526-532.

[98] Toppari, J.; Kaleva, M.; Virtanen, H.E. Trends in the incidence of cryptorchidism and hypospadias, and methodological limitations of

registry-based data. Hum Reprod. Update, 2001, 7, 282-286. [99] Pierik, F.H.; Burdorf, A.; Nijman, J.; de Muinck Keizer-Schrama,

S.M.; Juttmann, R.E.; Weber, R.F. A high hypospadias rate in The Netherlands. Hum. Reprod., 2002, 17, 1112-1115.

[100] Teilmann, G.; Juul, A.; Skakkebaek, N.E.; Toppari, J. Putative

effects of endocrine disrupters on pubertal development in the hu- man. Best Pract. Res. Clin. Endocrinol. Metab., 2002, 16, 105-121.

[101] Parent, A.S.; Teilmann, G.; Juul, A.; Skakkebaek, N.E.; Toppari, J.; Bourguignon, J.P. The timing of normal puberty and the age limits

of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr. Rev., 2003, 24, 668-693.

[102] Aksglaede, L.; Sørensen, K.; Petersen, J.H.; Skakkebaek, .N.E.; Juul, A. Recent decline in age at breast development: the Copenha-

gen Puberty Study. Pediatrics, 2009, 123, e932-939. [103] Köhrle, J. Environment and endocrinology: the case of thyroidol-

ogy. Ann. Endocrinol. (Paris), 2008, 69, 116-122. [104] Koopman-Esseboom, C.; Morse, D.C.; Weisglas-Kuperus, N.;

Lutkeschipholt, I.J.; Van der Paauw, C.G.; Tuinstra, L.G.; Brou- wer, A.; Sauer, P.J. Effects of dioxins and polychlorinated biphen-

yls on thyroid hormone status of pregnant women and their infants. Pediatr. Res., 1994, 36, 468-473.

[105] Hsu, P.C.; Lai, T.J.; Guo, N.W.; Lambert, G.H.; Leon Guo, Y. Serum hormones in boys prenatally exposed to polychlorinated

biphenyls and dibenzofurans. J. Toxicol. Environ. Health A., 2005, 68, 1447-1456.

[106] Hagmar, L.; Rylander, L.; Dyremark, E.; Klasson-Wehler, E.; Erfurth, E.M. Plasma concentrations of persistent organochlorines

in relation to thyrotropin and thyroid hormone levels in women. Int. Arch. Occup. Environ. Health. 2001, 74, 184-188.

[107] Takser, L.; Mergler, D.; Baldwin, M.; de Grosbois, S.; Smargiassi, A.; Lafond, J. Thyroid hormones in pregnancy in relation to envi-

ronmental exposure to organochlorine compounds and mercury. Environ. Health Perspect. 2005, 113, 1039-1045.

[108] Langer, P.; Kocan, A.; Tajtáková, M.; Petrík, J.; Chovancová, J.; Drobná, B.; Jursa, S.; Pavúk, M.; Koska, J.; Trnovec, T.; Seböková,

E.; Klimes, I. Possible effects of polychlorinated biphenyls and or- ganochlorinated pesticides on the thyroid after long-term exposure

to heavy environmental pollution. J. Occup. Environ. Med., 2003, 45, 526-532.

[109] Sandau, C.D.; Ayotte, P.; Dewailly, E.; Duffe, J.; Norstrom, R.J. Pentachlorophenol and hydroxylated polychlorinated biphenyl me-

tabolites in umbilical cord plasma of neonates from coastal popula- tions in Québec. Environ. Health Perspect., 2002, 110, 411-417.

[110] Lindhe, O.; Lund, B.O.; Bergman, A.; Brandt, I. Irreversible bind- ing and adrenocorticolytic activity of the DDT metabolite 3-

methylsulfonyl-DDE examined in tissue-slice culture. Environ. Health Perspect., 2001, 109, 105-110.

[111] Anderson M.S. Update in endocrine autoimmunity. J. Clin. Endo- crinol. Metab. 2008, 93, 3663-70.

[112] Owen C.J.; Cheetham T.D. Diagnosis and management of polyen- docrinopathy syndromes. Endocrinol. Metab. Clin. North. Am.,

2009, 38, 419-436. [113] Ahmed S.A.; Talal N. Sex hormones and the immune system–Part

2. Animal data. Baillieres Clin. Rheumatol., 1990, 4, 13-31. [114] Peeva E.; Zouali M. Spotlight on the role of hormonal factors in the

emergence of autoreactive B-lymphocytes. Immunol. Lett., 2005, 101, 123-143.

[115] Ahmed S.A.; Hissong B.D.; Verthelyi D.; Donner K.; Becker K.; Karpuzoglu-Sahin E. Gender and risk of autoimmune diseases:

possible role of estrogenic compounds. Environ. Health Perspect., 1999, 107(Suppl 5), 681-686.

[116] Zandman-Goddard G.; Peeva E.; Shoenfeld Y. Gender and auto- immunity. Autoimmun. Rev., 2007, 6, 366-372.

[117] Ahmed S.A. The immune system as a potential target for environ- mental estrogens (endocrine disrupters): a new emerging field.

Toxicology, 2000, 150, 191-206. [118] Rao T.; Richardson B. Environmentally induced autoimmune dis-

eases: potential mechanisms. Environ. Health Perspect., 1999, 107 Suppl 5, 737-742.

[119] Yurino H, Ishikawa S, Sato T, Akadegawa K, Ito T, Ueha S, In- adera H, Matsushima K. Endocrine disruptors (environmental es-

trogens) enhance autoantibody production by B1 cells. Toxicol. Sci., 2004, 81,139-147

[120] Guarneri F.; Benvenga S. Environmental factors and genetic back- ground that interact to cause autoimmune thyroid disease. Curr.

Opin. Endocrinol. Diabetes Obes., 2007, 14, 398-409. [121] Ablake, M.; Itoh, M.; Terayama, H.; Hayashi, S.; Shoji, S.; Naito,

M.; Takahashi, K.; Suna, S.; Jitsunari, F. Di-(2-ethylhexyl) phtha- late induces severe aspermatogenesis in mice, however, subsequent



Endocrine Disruptors and Human Health Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 9 855

antioxidant vitamins supplementation accelerates regeneration of

the seminiferous epithelium. Int. J. Androl., 2004, 27, 274-281. [122] Albertini, R.; Bird, M.; Doerrer, N.; Needham, L.; Robison, S.;

Sheldon, L.; Zenick, H. The use of biomonitoring data in exposure and human health risk assessments. Environ. Health Perspect.,

2006, 114, 1755-1762. [123] Angerer, J.; Ewers, U.; Wilhelm, M. Human biomonitoring: state

of the art. Int. J. Hyg. Environ. Health, 2007, 210, 201-228. [124] Wormuth, M.; Demou, E.; Scheringer, M.; Hungerbühler, K. As-

sessments of direct human exposure: the approach of EU risk as- sessments compared to scenario-based risk assessment. Risk Anal.,

2007, 27, 979-990. [125] Hines, E.P.; Calafat, A.M.; Silva, M.J.; Mendola, P.; Fenton, S.E.

Concentrations of phthalate metabolites in milk, urine, saliva, and Serum of lactating North Carolina women. Environ. Health Per-

spect., 2009, 117, 86-92. [126] Latini, G.; Wittassek, M.; Del Vecchio, A.; Presta, G.; De Felice,

C.; Angerer, J. Lactational exposure to phthalates in Southern Italy. Environ. Int., 2009, 35, 236-239.

[127] Mortensen, G.K.; Main, K.M.; Andersson, A.M.; Leffers, H.; Skakkebaek, N.E. Determination of phthalate monoesters in human

milk, consumer milk, and infant formula by tandem mass spec- trometry (LC-MS-MS). Anal. Bioanal. Chem., 2005, 382, 1084-

1092. [128] Fromme, H.; Gruber, L.; Schlummer, M.; Wolz, G.; Böhmer, S.;

Angerer, J.; Mayer, R.; Liebl, B.; Bolte, G. Intake of phthalates and di(2-ethylhexyl)adipate: results of the Integrated Exposure Assess-

ment Survey based on duplicate diet samples and biomonitoring data. Environ. Int., 2007, 33, 1012-1020.

[129] Seckin, E.; Fromme, H.; Völkel, W. Determination of total and free mono-n-butyl phthalate in human urine samples after medication of

a di-n-butyl phthalate containing capsule. Toxicol. Lett., 2009, 188, 33-37.

[130] Wensing, M.; Uhde, E.; Salthammer, T. Plastics additives in the indoor environment–flame retardants and plasticizers. Sci. Total

Environ., 2005, 339, 19-40. [131] Koo, H.J.; Lee, B.M. Estimated exposure to phthalates in cosmetics

and risk assessment. J. Toxicol. Environ. Health A., 2004, 67, 1901-1914.

[132] Latini, G. Monitoring phthalate exposure in humans. Clin. Chim. Acta, 2005, 361, 20-29.

[133] Heudorf, U.; Mersch-Sundermann, V.; Angerer, J. Phthalates: toxicology and exposure. Int. J. Hyg. Environ. Health., 2007, 210,

623-634. [134] Koch, H.M.; Rossbach, B.; Drexler, H.; Angerer, J. Internal expo-

sure of the general population to DEHP and other phthalates– determination of secondary and primary phthalate monoester me-

tabolites in urine. Environ. Res., 2003, 93, 177-185. [135] Koch, H.M.; Drexler, H.; Angerer, J. Internal exposure of nursery-

school children and their parents and teachers to di(2- ethylhexyl)phthalate (DEHP). Int. J. Hyg. Environ. Health., 2004,

207, 15-22. [136] Calafat, A.M. McKee RH. Integrating biomonitoring exposure data

into the risk assessment process: phthalates [diethyl phthalate and di(2-ethylhexyl) phthalate] as a case study. Environ. Health Per-

spect., 2006, 114, 1783-1789 [137] Koo, J.W.; Parham, F.; Kohn, M.C.; Masten, S.A.; Brock, J.W.;

Needham, L.L.; Portier, C.J. The association between biomarker- based exposure estimates for phthalates and demographic factors in

a human reference population. Environ Health Perspect., 2002, 110, 405-410.

[138] Blount, B.C.; Milgram, K.E.; Silva, M.J.; Malek, N.A.; Reidy, J.A.; Needham, L.L.; Brock, J.W. Quantitative detection of eight phtha-

late metabolites in human urine using HPLC-APCI-MS/MS. Anal. Chem., 2000, 72, 4127-4134.

[139] Hatch, E.E.; Nelson, J.W.; Qureshi, M.M.; Weinberg, J.; Moore,

L.L.; Singer, M.; Webster, T.F. Association of urinary phthalate metabolite concentrations with body mass index and waist circum-

ference: a cross-sectional study of NHANES data, 1999-2002. En- viron. Health., 2008; 7, 27.

[140] Latini, G.; De Felice, C.; Presta, G.; Del Vecchio, A.; Paris, I.; Ruggirei, F.; Mazzeo, P. In utero exposure to di-(2-

ethylhexyl)phthalate and duration of human pregnancy. Environ. Health Perspect., 2003, 111, 1783-1785.

[141] Meeker, J.D.; Calafat, A.M.; Hauser, R. Di(2-ethylhexyl) phthalate metabolites may alter thyroid hormone levels in men. Environ.

Health Perspect., 2007, 115, 1029-1034. [142] Hokanson, R.; Hanneman, W.; Hennessey, M.; Donnelly, K.C.;

McDonald, T.; Chowdhary, R.; Busbee, D.L. DEHP, bis(2)- ethylhexyl phthalate, alters gene expression in human cells: possi-

ble correlation with initiation of fetal evelopmental abnormalities. Hum. Exp. Toxicol., 2006, 25, 687-695.

[143] Jaakkola, J.J.; Knight, T.L. The role of exposure to phthalates from polyvinyl chloride products in the development of asthma and al-

lergies: a systematic review and meta-analysis. Environ. Health Perspect., 2008, 116, 845-853.

[144] Palleschi, S.; Rossi, B.; Diana, L.; Silvestroni, L. Di(2- ethylhexyl)phthalate stimulates Ca(2+) entry, chemotaxis and ROS

production in human granulocytes. Toxicol. Lett., 2009, 187, 52-57. [145] Wittassek, M.; Angerer, J.; Kolossa-Gehring, M.; Schäfer, S.D.;

Klockenbusch, W.; Dobler, L.; Günsel, A.K.; Müller, A.; Wies- müller, G.A. Fetal exposure to phthalates – a pilot study. Int. J.

Hyg. Environ. Health., 2009, 212(6), 685-92. [146] Fabjan, E.; Hulzebos, E.; Mennes, W.; Piersma, A.H. A category

approach for reproductive effects of phthalates. Crit. Rev.Toxicol., 2006, 36, 695-726.

[147] Wirth, J.J.; Rossano, M.G.; Potter, R.; Puscheck, E.; Daly, D.C.; Paneth, N.; Krawetz, S.A.; Protas, B.M.; Diamond, M.P. A pilot

study associating urinary concentrations of phthalate metabolites and semen quality. Syst. Biol. Reprod. Med., 2008, 54, 143-154.

[148] Swan, S.H. Environmental phthalate exposure in relation to repro- ductive outcomes and other health endpoints in humans. Environ.

Res., 2008, 108, 177-184. [149] Lovekamp-Swan, T.; Davis, B.J. Mechanisms of phthalate ester

toxicity in the female reproductive system. Environ. Health Per- spect., 2003, 111, 139-145.

[150] Latini, G.; Del Vecchio, A.; Massaro, M.; Verrotti, A.; De Felice, C. Phthalate exposure and male infertility. Toxicology, 2006, 226,

90-98. [151] McKee, R.H.; Butala, J.H.; David, R.M.; Gans, G. NTP center for

the evaluation of risks to human reproduction reports on phthalates: addressing the data gaps. Reprod. Toxicol., 2004, 18, 1-22.

[152] Heudorf, U.; Mersch-Sundermann, V.; Angerer, J. Phthalates: toxicology and exposure. Int. J. Hyg. Environ. Health, 2007, 210,

623-634. [153] Center for Devices and Radiological Health, U.S. Food and Drug

Administration. Safety Assessment of Di(2-ethylhexyl)phthalate (DEHP) Released from PVC Medical Devices. Available at [accessed 5 September 2001]

[154] Koch, H.M.; Preuss R, Angerer J. Di(2-ethylhexyl)phthalate (DEHP): human metabolism and internal exposure—an update and

latest results. Int. J. Androl., 2006, 29, 155-165. [155] Kamrin, M.A. Phthalate risks, phthalate regulation, and public

health: a review. J. Toxicol. Environ. Health B. Crit. Rev., 2009, 12, 157-174.

[156] Wormuth, M.; Demou, E.; Scheringer, M.; Hungerbühler, K. As- sessments of direct human exposure: the approach of EU risk as-

sessments compared to scenario-based risk assessment. Risk Anal., 2007, 27, 979-990.



Received: March 22, 2010 Revised: May 11, 2010 Accepted: May 12, 2010

"Looking for a Similar Assignment? Get Expert Help at an Amazing Discount!"