endocrine disrupting chemicals: human exposure and health risks
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Endocrine Disrupting Chemicals: HumanExposure and Health RisksMIHI YANG a , MI SEON PARK a & HO SUN LEE aa College of Pharmacy , Sookmyung Women's University , Seoul,Republic of KoreaPublished online: 06 Feb 2007.
To cite this article: MIHI YANG , MI SEON PARK & HO SUN LEE (2006) Endocrine DisruptingChemicals: Human Exposure and Health Risks, Journal of Environmental Science and Health,Part C: Environmental Carcinogenesis and Ecotoxicology Reviews, 24:2, 183-224, DOI:10.1080/10590500600936474
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Journal of Environmental Science and Health Part C, 24:183–224, 2006Copyright C© Taylor & Francis Group, LLCISSN: 1059-0501 (Print); 1532-4095 (Online)DOI: 10.1080/10590500600936474
Endocrine DisruptingChemicals: Human Exposureand Health Risks
Mihi Yang, Mi Seon Park, and Ho Sun LeeCollege of Pharmacy, Sookmyung Women’s University, Seoul, Republic of Korea
Endocrine disrupting chemicals (EDCs) have been emphasized due to their threatsin fertility, intelligence, and survival. For the last decade, many researchers have in-vestigated EDC-health outcome. However, EDC responses in human were not clearlyclarified through experimental and epidemiological data. Therefore, considering par-ticular status of EDC endpoints, we suggest that one of the best ways to prevent un-known health risks from EDCs is to perform exposure monitoring or to do surveillancefor EDC release into the environment. For this purpose, this review considers expo-sure status of EDCs, and EDC-related health risks, focusing on the mainly highlightedEDCs, such as dioxins/PCBs, DDT/DDE, bisphenol A, phthalates, alkylphenols, andphytoestrogens. We also reviewed tobacco, a mixed source of EDC-related endocrinedisorders.
Key Words: Endocrine Disrupting Chemicals; Dioxins; PCBs; Bisphenol A; Exposure;Phytoestrogens; Biological Monitoring; Health Risk; Teratogenicity
INTRODUCTION
Endocrine disrupting chemicals (EDCs), which are produced from industrialproducts and their byproducts or wastes, disperse into the environment andthreaten with health risks of various undesired endocrine disorders. EDCshave been emphasized due to publication of Our Stolen Future in 1996 (1),which warned about EDCs’ threats in fertility, intelligence, and survival asdichlorodiphenyl trichloroethane (DDT) had due to that of Silent Spring in1962 (2), which warned about DDT’s threats in ecosystems. Since the impact ofOur Stolen Future, the general public has become worried about health risks ofEDCs, and proper regulations for EDCs have become required for governments.
Address correspondence to Prof. Mihi Yang, Department of Toxicology, College of Phar-macy, Sookmyung Women’s University, 53-12 Chungpa-Dong, Yongsan-Ku, Seoul, 140-742, Republic of Korea. E-mail: [email protected]
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At the first step, each developed country, e.g., OECD countries, has spent mil-lion dollar scales of research grants per year to clarify EDC response end-points, i.e., toxicity and final health outcomes, for the last 10 years (3). As aresult, many researches showed apparent associations between EDC exposureand various EDC-related health outcomes. However, some of these findings arecontroversial (e.g., time trend studies on ‘decline of sperm number accordingto years’ (4–5)) whereas in other studies, clear-cut health outcomes inducedby EDCs have yet to be found. Thus, regulatory agencies for EDCs are of-ten confronted with difficulty to control EDCs and with blame to waste publicmoney.
Concerning endpoint problems in EDC studies, there are several reasonssuggested. The first reason is the possibility of hormesis in EDCs. For example,an inverted-U dose-response phenomenon in diethylstilbestrol dose-responserelationship was reported by vom Saal et al. in limited animal studies (6). Thesecond is the mixed exposure to various EDCs in daily life. Compared to an-imal studies with treatment of a particular EDC, people are simultaneouslyexposed to various EDCs, actions of which may be different or inverse fromeach other. The third reason is the lack of clarification of the action mecha-nisms of EDCs due to limitations of studies. Due to these kinds of reasons,EDCs may not easily show any endocrine disorders in humans through designedstudies.
Therefore, this review considers analyses of exposure status of EDCs, andof reported EDC-related health risks, focusing on the main highlighted EDCs,such as dioxins/PCBs, DDT/DDE, bisphenol A, phthalates, alkylphenols, andphytoestrogens. We also reviewed tobacco, a mixed source of EDC related en-docrine disorders.
HUMAN EXPOSURE TO EDCs
PCBs/DioxinsPolychlorinated biphenyls (PCBs: Figure 1) were produced from the 1930s,
with a particularly large volume, to the 1970s, producing a complex mixturecontaining 60–90 congeners (7). Because of their insulating and nonflammableproperties, PCBs were marketed for nearly 40 years as heat exchange anddielectric fluids. Commercial PCB products were always mixtures of differ-ent PCB congeners and were usually contaminated with small amounts ofpolychlorinated dibenzodioxins (PCDDs) (8). Between 1930 and 1979, over 600million kg of PCBs were used in North America alone, 15% of which enteredthe environment through legal and illegal use, disposal, and accidental releases(7). Since PCBs are highly resistant to degradation, they may remain in soilsand bodies of water for many years, and are passed up the food chain.
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Figure 1: Structures of emphasized EDCs.
When the ability of PCBs to accumulate in the environment and to causeharmful effects became apparent, production of PCBs was banned in Sweden(1970), Japan (1972) and the USA (1976) (7). The current major source ofambient PCB exposure seems to be environmental cycling of PCBs previouslyreleased into the environment, since the 1.25 billion pounds of PCBs producedin the U.S. between 1929 and 1977 and approximately 450 million pounds ofthem have found their way into the environment (8). PCBs have been releasedinto the environment from several sources, e.g., poorly maintained hazardouswaste dumps and city landfills, illegal or improper dumping of hydraulic flu-ids/coolants, and long distance travel in the air and subsequent deposition inareas far away from where they were released (9). Since the 1970s, researchershave noticed a decrease in PCB concentrations in human serum. PCB levels
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in blood and breast milk were continuously monitored from 1987 to 2001 inGermany (10, 11). As a result, finding high levels of toxic equivalence (TEQ)levels decreased to approximately half of the original values.
Relatively high concentrations of PCBs were detected in increasing orderin seawater, plankton, small fish, bigger fish and fish eating animals. Humansand their suckling are also situated at the top of food chain, as humans ingestconsiderable amounts of fish and feed babies with contaminated mother’s breastmilk (10). Fish, beef, inner organs, eggs, cheese, and other fat-containing foodsof animal origin may contain up to 1–2 mg PCBs/kg (12). Average dietary intakeof PCBs is estimated to be around 15 µg/day or 0.25 µg/kg bw/day in Finland.Depending on the preference of fish eating, some sub-groups have higher intakeof PCBs as compared to the average (12–13).
The estimated median intakes of PCBs from the foods including meat, dairyproducts, eggs, fish, oils and fats and vegetables and regional diets are listedin Figure 2: The high contribution from fish is clearly related to the relativelyhigh concentrations of PCBs in this food group. It has the greatest effect onthe Far Eastern diet, which contains more fish than the other diets. The largecontribution from meat in the North American diet is also striking.
In addition, exposure to PCBs can occur through various sources ofcontaminated water including wells, surface water and swimming areas. SincePCBs cannot dissolve well in water, these sources of exposure are not consid-ered nearly as important as the diet. Very small amounts of PCBs are foundin almost all soils. Children playing in soils near certain hazardous waste sitesmay be exposed to relatively high levels of PCBs. This may occur from eatingthe soil or by absorbing them across the skin (8–9).
Figure 2: Estimated intake of PCBs in regional diets (pg TEQ/day) (14); aNorth America,data from USA & Canada; bOceania, data from New Zealand; cFar east, data from Japan.
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Another source of PCB exposure is from workplaces. Workplace exposurecan occur during repair and maintenance of PCB transformers, accidents, fires,spills, or disposal of PCB-containing material by breathing contaminated airand touching materials containing PCBs. Old appliances and electrical equip-ment are also thought to be the primary source of household contamination,since they may contain PCBs. PCB levels in indoor air are often much higherthan in outdoor air (8, 9).
A notorious episode of PCB is the Yusho (Oil disease), which occurred atKitakyushu, Japan in 1968. The cause of the accident was a rice bran oil plantof the Kanemi warehouse company. PCB was used as a heating medium bythe manufacturing process of the edible oil and leaked from the hole of thecorroded pipe in the factory, and it mixed with oil (15). The Yusho occurredby ingestion of the PCBs-contaminated rice oil. More than 1,800 patients havebeen registered as having Yusho and around 300 patients have already died (16).Clinical observation showed that typical symptoms of Yusho have decreased.Teratogenic effects observed were the unusual increase of still and live births ofabnormal coloring babies also called “black” or “cola coloring” babies. Anotherteratogenic effect was nail deformity among living babies. Time trend symptomsamong Yusho patients were numbness of extremities, fatigue and headaches(17). This episode resulted in a civil action against pollution following Minamataor Itai-itai disease in Japan. Lawsuits that appealed for Yusho at Kanemi, andthe country by the patient were concluded by the concord and the withdrawalfor 87 years (15).
The term “dioxins” is commonly used to refer to a group of 75 polychlori-nated dibenzo-p-dioxin (PCDD) and 135 polychlorinated dibenzofuran (PCDF)congeners, of which less than 20 are considered to be biologically active (18).Total dioxin emission level as TEQ was estimated to be approximately 14,000 gTEQ/yr in 1987, 3,250 g TEQ/yr in 1995 and 1,100 g TEQ/yr in 2004, an ap-proximate decline of nearly 92% in quantified emissions between 1987 and 2004(19–21). The largest sources of emissions were ‘municipal and medical wasteincinerators’, which together accounted for more than 85 and 65% of total dioxinreleases in 1987 and 1995, respectively (19, 20). Other significant quantifiedsources of dioxin releases include domestic fires and bonfires, forest fires andinternal combustion in automobile engines. Dioxins are also generated as tracecontaminants during the synthesis of many organochlorine compounds andduring some industrial processes (20). The presence and persistence of diox-ins in the general environment, and their chemical and physical properties—including high lipophilicity and low volatility—result in the tendency of dioxinsto accumulate in the food chain (Figure 3). The half-life of dioxin is about 8 years.It has been estimated that more than 90% of current human exposure to diox-ins among the general population occurs via food consumption, primarily fromfoods containing animal fats and children get additional exposure from breastmilk (19).
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Figure 3: Anthropogenic sources of dioxins (22).
The U.S. Environmental Protection Agency (USEPA) presented estimatesof mean dietary intake levels in each of the two dioxin- reassessment drafts(1994 and 2000) (19, 20). The 2000 estimates of 0.6 pg PCDD/F TEQ/kg/day islower than the 1994 estimate of 1.7 pg/kg/day. The 1994 estimate is generallytaken to represent intake levels from the mid- to late-1980s, while the 2000estimate is based on data from the early- to mid-1990s. According to the USEPAassessment, beef, milk, and dairy account for approximately 50% of the TEQintake. Fresh water and marine fish together are the next largest contributorsto intake dioxins. Poultry and pork account for most of the remainder of theestimated intake; vegetables and grains are generally low in dioxin contentcompared to foods containing animal fats (19).
Data from a food monitoring program of the German government docu-mented a drop in estimated mean intake of dioxins and furans from approxi-mately 2 pg TEQ/kg/day in the late 1980s to approximately 1 pg TEQ/kg/day in1994–5 (23). Another study from Beck et al. (24) shows dietary intake of TEQhas been 2.3 pg/kg bw/day, but for a breast-fed child the dose is remarkablyhigher, 142 pg TEQ/kg bw/day.
In the case of Japan, Maitani et al. found the average daily intake of dioxinsincluding PCDDs, PCDFs and coplanar-PCBs, to be 1.49 pg TEQ/kg bw/day in2002: The average daily intake of dioxin (PCDD/Fs) was 0.52 pg TEQ/kg/dayand that of Co-PCBs was 0.97 pg TEQ/kg/day. The intake of dioxins in 2000 and2001 was 1.45 and 1.63 pg TEQ/kg/day, respectively. Thus, the daily intake hasremained almost constant at 1.5 pg TEQ/kg/day during the last three years.However, analytical results of total diet study samples from the Kansai areain Japan, which had been conserved by the Japan National Institute of Health
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Sciences (NIHS) until the time of analysis, demonstrated that the average dailyintake of dioxins decreased between 1977 and 2002 (25).
The most serious accidental explosion of PCDD/F exposure occurred in 1976at a chemical plant in Meda, near Seveso, northern Italy. The explosion releaseda toxic vapor cloud containing 3,000 kg of various chemicals and about 100 g to20 kg of 2,3,7,8-TCDD (17). After the incident, the first health effects occurred afew hours later when children showed burn-like skin lesions. Five days later, awidespread death of animals such as birds and rabbits occurred. Approximately37,000 people are believed to have been exposed to the chemicals at that time(17, 26).
Several authoritative agencies and scientific organizations have concludedthat 1–4 pg TEQ/kg/day of TCDD is likely to be without adverse health effects(19). Conversely, the USEPA has suggested that TCDD doses in the range of1 pg/kg/day, and even far lower, may pose a significant health risk (19, 20).The overall level of human exposure to dioxins, furans and dioxin-like PCBsis declining dramatically. Figure 4 shows that the percentage of exposure toTCDD, is greatly reduced from previous levels. By 2010, it is projected thatthere will be virtually no exposure to TCDD (27).
DDT/DDEDDT was synthesized in 1874, but its insecticidal properties were not dis-
covered until 1939, and its large-scale industrial production started in 1943
Figure 4: Reductions in average exposure to dioxins/furans/PCBs over time (pg TEQ/kgbw/day) (27).
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(28). It has been used widely on agricultural crops as well as for “vectorcontrol”—the control of insects that carry such diseases as malaria and typhus,and, in powder form, as a directly applied louse-control substance in people(29). In the early 1960s, approximately 400,000 tons of DDT were annuallyconsumed (28). People began to notice that DDT could cause damage to wildlifeand had the potential to harm human health in the 1960s (2). That led to in-creased international attention to DDT’s impact on wildlife and humans, whichin turn triggered a number of international restrictions on the pesticide, e.g.,Sweden banned DDT in 1970, the USA in 1972, and the UK in 1986 (29, 30).It also led to increased awareness of the long-term effects of other pesticidesand industrial chemicals. Nevertheless, DDT is still used in many parts of theworld, and its persistence in the environment poses a danger for ecosystemsand human beings (29).
When DDT was sprayed, it can drift sometimes for long distances and evap-orate or attach to wind-blown dust. In the environment, DDT breaks down top,p′-DDE (bis[4-chlorophenyl]-1,1-dichloroethene) (Figure 1), an extremely sta-ble compound that resists further environmental breakdown or metabolism byorganisms. The general population is exposed to DDT mainly through food,whereas occupational exposures are mainly through inhalation and dermalcontact. DDT and DDE can also be transferred from the placenta and breast-milk to fetuses and infants. DDT and DDE are highly soluble in lipids: Theirconcentrations are much higher in human adipose tissues than in breast-milk,and higher in breast-milk than in blood or serum. DDT and DDE concentra-tions showed age-dependency (30). In addition, it may take between 10 and 20years for DDT to disappear from an exposed individual, but that DDE wouldpossibly persist throughout the life span (28).
With the use of DDT declining since the 1970s, concentrations of DDT andits metabolites in human tissue have fallen greatly in worldwide. DDT lev-els are usually much lower in developed nations than in developing countries(30). Many developed nations restricted or banned DDT in the 1970s, whilerestrictions in the developing world were not common until the 1980s (29).
Currently, people in Europe, the USA, Canada, Australia, New Zealand,and Japan have lower concentrations of DDT compounds in their breastmilkthan before. For example, the total DDT concentration in breast-milk fat was2.9 µg/g in 1972 and 0.3 µg/g in 1992 in Sweden (30). In the case of Canada, thetotal DDT concentration in breast-milk fat was 2.9 µg/g, 1.8 µg/g and 0.3 µg/g in1970, 1978, and 1986, respectively (31, 32) (Figure 5). However, in Central andSouth America, Mexico, Africa, and some Asian countries, where DDT had beenused for vector control in the past 5–10 years, DDT concentrations in humantissues remain still high: For example, the total DDT concentration in breast-milk fat in Mexico was 5.7 µg/g in 1994–5 and 4.7 µg/g in 1997–8 (30, 33). InSouth Africa, continuous DDT spraying has resulted in a DDE concentrationrange of 5.2–7.7 µg/g in breast-milk fat in the treated area (30,34): The mean
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Figure 5: Concentration of DDT in breast milk (µg/kg in milk fat) (31).
concentration of serum DDE in a DDT-treated area there was 103 µg/L, whereasthat in an untreated area was 6 µg/L in South Africa. In addition, some Mexicandata revealed that the geometric mean of total DDT was 104.48 µg/g in adiposetissue of the DDT sprayers (30,35); the value was less than 1 µg/g among adiposetissues of the general population in Finland, the USA, and Canada (30).
Bisphenol ABisphenol A (2,2-bis(4-hydroxyphenyl)propane) is one of the largest
volume-produced chemicals in the world with an annual excess of 6 billionpounds in 2003, with continued growth in production expected (36). BisphenolA-derived polycarbonate and epoxy resins have been used for drinking watercontainers, baby bottles, dental sealing, and coating food cans. Bisphenol Aitself has been widely used in plastic manufacture and as an antioxidant inbrake fluid, etc. (37). Thus, people can be easily and continuously exposed tobisphenol A in their daily environment.
Bisphenol A has been detected in industrial wastewater and in fresh water.Accumulation of bisphenol A in organisms may be small due to short half-life(6 hr). It has been observed that bisphenol A can be dissolved from the products
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Table 1: Estimated daily intakes of bisphenol A from food contact applications ofepoxy-resins (µg/kg bw/day).
EstimatedDaily Concentration BPA intakes
Age (year) Food type intakes of BPA (µg/kg) (µg/kg bw/day)
Infant (0–0.33), 4.5 kg Powdered milk 0.7 L 10 1.6Toddler (0.5–1), 8.8 kg Powdered milk 0.7 L 10 0.8Toddler (0.5–1), 8.8 kg Canned food 0.38 kg 20 0.85Child (4–6), 18 kg Canned food 1.05 kg 20 1.2Adult, 60 kg Canned food 1.05 kg 20 0.37Adult, 60 kg Wine 0.75 L 9 0.11
during their use (12). Bisphenol A-derived epoxy resins are used widely in thefood packaging industry for the inner coating of food cans to prevent corro-sion. Leaching of bisphenol A can be facilitated when canned food is cookedor sterilized at high temperatures. Bisphenol A-based resins are also used assusceptors to achieve food browning in some packages designed for microwavecooking (38). Table 1 provides the estimates of daily intake of bisphenol A, as aresult of food contact applications of epoxy-resins (39).
Since 2000, our group has performed biological monitoring of bisphenol Ain urine. Our results showed that the median levels of urinary bisphenol A inKoreans have decreased: 9.54 µg/L in adults, 2000 (37); 4.20 µg/L in adults,2001; 0.97 µg/L in children, 2002 (Yang et al. unpublished data). Comparedto other EDCs such as PCBs or DDTs, the production volume of bisphenol Ahas not decreased (40). In addition, the analysis methods for bisphenol A areon-going for establishment. Therefore, we suggest that the reason of decreaseof bisphenol A in monitoring results is mainly due to development of analysistechniques rather than reduction of use of bisphenol A.
A Japanese group recently reported a median daily urinary excretion of1.2 µg/day and maximum daily intake of bisphenol A per body weight wasestimated to be 0.23 µg/kg/day based on the measurement of urinary bisphe-nol A (41). In addition, the Centers for Disease Control and Prevention (CDC)reported bisphenol A concentrations in spot urine samples from 394 adults inthe USA (42). Based on a median concentration of 1.32 µg bisphenol A/g crea-tinine, the median daily bisphenol A intake can be estimated as approximately1.6 µg/person/day, which indicates that human exposures to bisphenol A in theUSA and Japan are very similar. From these biological monitoring studies, typ-ical long-term human exposure to bisphenol A in developed countries is likelyto be in the range of 20–30 ng/kg bw/day, as approximately 400–2,000 times be-low lifetime daily intake levels are expected to have no adverse effect on health(43). That is, the USEPA has set a reference dose of 50 µg/kg bw/day and theEuropean Commission’s Scientific Committee on Food has set a tolerable dailyintake (TDI) of 10 µg/kg bw/day (39, 43).
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PhthalatesPhthalates are a family of industrial compounds, dialkyl or alkyl/aryl esters
of 1,2-benzenedicarboxylic acid. Since the 1930s, phthalates have been used fora variety of purposes including industrial solvents, lubricants, additives in thetextile industry and in pesticide formulations, and components in consumerproducts like deodorants, perfumes or hair sprays (44). Because of their largeand widespread use, phthalates are today considered as ubiquitous environ-mental contaminants (45). Phthalates can easily elute and transfer from pack-aging to food products and the environment (46). Physical properties and theirapplications depend on the length and branching of the dialkyl or alkyl/arylside chains (44). Di-(2-ethylhexyl) phthalate (DEHP) is the most important ph-thalate, and more than 2 million tons of DEHP alone are produced each yearworldwide (45, 47). Other important phthalate are diethylphthalate (DEP),di-iso- and di-n-butylphthalate (DiBP, DnBP), butylbenzyl-phthalate (BBzP),di-iso-nonylphthalate (DiNP) and di-n-octylphthalate (DnOP) (45, 48).
The primary route of human phthalate exposure to the general populationis ingestion for phthalates that are used mainly as plasticizers, such as DEHP,oral exposures predominate (44, 47). However, low molecular weight phthalatescan be absorbed percutaneously and the more volatile congeners can be inhaled(49). Dermal and inhalative exposures are considered to be the major route ofexposure to DEP that is found in hygiene products such as soap, shampoo, andconditioners (44, 48). Exposure of the general human population to DEHP hasbeen estimated to be in the range of 3 to 30 µg/kg of body weight/day exclud-ing occupational exposure, medical exposures, and non-dietary ingestions inchildren (44). The major source of general population exposure is thought to bedietary, followed by indoor air (Table 5). These estimates already exceed chronicexposure levels believed to be tolerable for the general population: TDI valuesettled by the EU Scientific Committee for Toxicity, Ecotoxicity and the Envi-ronment (CSTEE) is 37 µg/kg body weight/day, and the RfD of the USEPA is20 µg/kg bw/day (44, 45). In addition, the transgressions of TDI for DEHP areaccompanied by considerable ubiquitous exposures to DnBP and BBzP. Expo-sures to other phthalates, including DiNP and diisodecylphthalate (DiDP), areusually assumed to be lower primarily because production volumes are lower.
Table 2: Estimated DEHP intake in Canada (µg/kg bw/day).
Indoor DrinkingAge (year) Ambient air air water Food Soil Total
0.0–0.5 0.00003–0.0003 0.86 0.13–0.38 7.9 0.00006 8.9–9.10.5–4 0.00003–0.0003 0.99 0.06–0.18 18 0.00004 195–11 0.00004–0.0004 1.2 0.03–0.10 13 0.00014 1412–19 0.00003–0.0003 0.95 0.02–0.07 7.2 0.00004 8.220–70 0.00003–0.0003 0.85 0.02–0.06 4.9 0.00003 5.8
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However, increasing exposures to these phthalates have to be assumed for thefuture, since they are used as replacements for DEHP and production numbersrise (44). Therefore, future control criteria should be considered for exposure tothe DiNP and DiDP.
Dietary exposure may vary from country to country because DEHP is in-troduced through various food processing and packing techniques that differinternationally. The synthesis and analysis metabolism to secondary metabo-lites like mono-(2-ethyl-5-hydroxyl)-phthalate, mono-(2-ethyl-5-oxohexyl) ph-thalate, and mono-(2-ethylhexyl)-phthalate in urine improved the chances toestimate the exposure of the population to DEHP (50). Table 2 showed that es-timated daily intake of DEHP in Canada (51) and similarly, estimated DEHPintake concentrations in the U.S. is 5.0, 7.3, 25.8, 18.9, 10.0 and 8.2 µg/kgbw/day in formula-fed infant, breast-fed infant, toddler, child, teen and adult,respectively (52). Particularly, exposure in children is thought twice as high asthat in adults with respect to their body weight.
Alkylphenols4-Alkylphenol ethoxylates (APEs) are a widely used class of nonionic sur-
factants with an annual worldwide production of approximately 650,000 tons(53). Demand for APEs is increasing at a rate of 2% per year in the USA(54). Nonylphenol ethoxylates (NPEs) and octylphenol ethoxylates (OPEs) aretwo of the most common surfactants in the marketplaces. NPEs accounts forapproximately 80% of APEs, and OPEs account for most of the remainder (55).They are synthesized by addition of ethylene oxide to nonylphenols (NPs) underalkaline conditions leading to NPEs with varying lengths of the ethoxylateschains (53).
Production of industrial and household liquid detergents is the major ap-plication for NPs, and is responsible for the anticipated steady growth for NPconsumption. Other applications include lubricant oil addictives and phosphateantioxidants for rubber and plastics (54). Most of the NPEs are disposed forsubsequent treatment at sewage treatment plants. During the different stepsof sewage treatment, a complex biodegradation process of NPEs takes place,leading to the formation of several biorefractory metabolites. Particularly, theformed NPs are persistent and toxic. After release in the aquatic environment,they accumulate in aquatic organisms (53).
Since the exposure to these substances in wildlife and human exposure ismainly through water, the occurrence of alkylphenols (APs) has been investi-gated in a variety of rivers, lakes, estuaries and coastal waters (55). The APEsoccured in surface water and sediments from the Pearl River Delta and adjacentNorthern South China Sea and were found in all of the sediment samples. AsAPs in water are still hydrophobic, they deposit to the bottom sediments. Thus,the sediment samples were contaminated with NPs and octylphenols (OPs)
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Endocrine Disrupting Chemicals 195
ranging from 59 to 7,808 µg/kg and from 1 to 93 µg/kg, respectively. NP con-centrations in waters ranked from ‘below detection level’ to significantly highconcentration of 644 µg/L in a Spanish study (54). Ferrara et al. investigated theoccurrence of APs and APEs in 8 marine species from the Adriatic sea, Italy andtried to estimate the corresponding intake for the Italian population. As a result,estimated daily intakes of NPs, OPs, and OPEs were approximately 12, 0.1 and0.1 µg/day, respectively, in Italian adults living along the Adriatic Coast (56).
Data concerning human exposure monitoring to NPs are scarce. NPs weremeasured in the urine samples using column-switching liquid chromatogra-phy/mass spectrometry (GC/MS), and also analyzed in urine plasma sampleswith GC/MS. However, the NP concentration in real urine was below the limitof detection (0.2 ng/ml) (42).
One possible route of human APEs exposure is residue of endocrine disrupt-ing compounds in food. In a German study, they measured the levels of NPsin 39 foods and beverages including fruits and vegetables, dairy products, fishand meat, bread, pasta, beer, coffee, and chocolates, which were purchased fromGerman supermarkets (53). As a result, NPs were detected in several foodstuffswithin the range 0.1–19.4 µg/kg. The highest concentrations of NPs were foundin apples, tomatoes, and fatty foods such as fish and meat. The average daily in-take of NPs via food for an adult from the data is thought to be around 7.5 µg/day.
As mentioned above, biological monitoring of APs was not confirmed enoughand their analyzing methods were not fully established. Therefore, consideringcontamination statutes of APs, their proper biological monitoring is urgentlyrequired.
PhytoestrogensSome naturally occurring compounds present in plants have been found to
possess oestrogenic properties. These chemicals have been termed phytoestro-gens. Compared to other endocrine disruptors, phytoestrogens were emphasizedas beneficial compounds for prevention of menopausal syndromes, osteoporo-sis, cancer, and heart disease (57). However, the interests in phytoestrogenshave been changed by the realization of their potential of endocrine disruption,e.g., the apprehension that soy-milk fed infants are not as safe or effective aspreviously thought (58).
Figure 6 shows classes of phytoestrogens (59). Three classes of flavonoid,coumestans, prenylated flavonoids and isoflavones are phytoestrogens thatpossess the most potent oestrogenic activity among phytoestrogens. A classof non-flavonoid phytoestrogens, i.e., the lignans has also been identified. Theprinciple difference between phytoestrogens and xenoestrogens is that theformer are easily metabolized and excreted, whereas the latter tend to bioaccu-mulate (12). Phytoestrogens possess oestrogenic properties due to their struc-tural similarities to the hormone oestradiol (60). The structural similarities
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196 M. Yang et al.
Figure 6: Classification of dietary estrogens (60).
between members of the four main groups of phytoestrogen identified aboveand oestradiol are shown in Figure 7 (58).
The majority of phytoestrogens belong to a large group of substituted phe-nolic non-steroidal compounds known as flavonoids. Flavonoids are present inmany plants and constitute up to 7% of the dry weight of some plants (60).Humans are exposed to phytoestrogens via daily diet such as cereals, rice andsoybeans.
The main classes of phytoestrogens and common dietary sources are shownin Table 3 (60). The most prevalent dietary isoflavones include genistein,daidzein, glycitein, biochanin A and formononetin. Isoflavones are found al-most exclusively in the family leguminosae. Soybeans are a very rich source ofisoflavones, particularly genistein and daidzein, and glycitein. Soybeans con-tain approximately 2 g of isoflavones/kg fresh weight (60). However, it mustbe emphasized that the isoflavone content of soy products can vary betweenamong soybean varieties and through soybean processing. Biochanin A and for-mononetin are generally less prevalent in soy; however, they are found mostlyin clover and alfalfa sprouts.
The coumestans of which coumestrol is the most common form, are struc-turally related to isoflavones (Figure 7B and C). They have been found in highconcentrations in clover and fresh alfalfa sprouts with coumestrol contents of5.6 and 0.7 mg/g dry weight, respectively (60).
Lignans are found in foodstuffs such as grains, seeds and other fiber richfoods in the highest concentration. The highest production of lignans was found
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Endocrine Disrupting Chemicals 197
Figure 7: Structures of similarity in estradiol and phytoestrogens (58).
in oilseeds including flaxseed and unhulled soybeans (20.5 mg/100 g), withlesser amounts found in dried seaweeds (0.9 mg/100 g), whole legumes (0.6mg/100 g), cereal barns (0.5 mg/100 g), legumes hulls (0.4 mg/100g), whole graincereals (0.3 mg/100 g), vegetables (0.14 mg/ 100 g), and fruits (0.08 mg/100 g).The prenylated flavonoids have been found in high concentration in hops (61).
Dietary phytoestrogens intake depends on the type and composition of food-stuffs consumed in different countries (60). For example, Figure 8 shows thecomparison of estimated dietary isoflavones intake between Western and East-ern populations. Eastern people have significantly higher intakes of phytoe-strogens than Western people. These differences are generally attributed tothe usage and consumption of soy and soy-based foods (62–69).
The Committee on Toxicity of Chemicals in Food, Consumer Products andthe Environment (COT) estimated exposure of infants to phytoestrogens (60):
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Table 3: Classes of phytoestrogens and common dietary source
Phytoestrogen class Example of dietary source
IsoflavoneGenistein Legumes, lentils, chick, soybeanDaidzeinGlyciteinFormononetinBiochnin A
CoumestansCoumestrol Young sprouting legumes, e.g., clover and alfalfa sprouts
LignansMatairesinol Most cereals, linseed, fruit and vegetablesSecoisolariciresinolLariciresinolIsolariciresinol
Prenylated flavonoids6-prenylnaringenin Beer (hops)8-prenylnaringeninXanthohumolIsoxanthohumol
The estimated exposure level is dependent on whether the infant is fed breastor formula milk. Isoflavones levels corresponding to approximately 2–32 µg/Lwere detected in the breast milk of mothers with a vegetarian diet. In thecase of cow’s milk-based formula, isoflavones were not detectable. However,these concentrations were substantially lower than those in soy-based infantformulae (18–41 mg isoflavones/L made up formula) or weaning foods (18–78 mgisoflavones/kg): Mean intakes of isoflavones from soy-based infant formula areestimated at 4.5–5 mg/kg bw/day. The concentration is higher than the levels,which are associated with hormonal effects in premenopausal women. Thus, theCOT recommended that appropriate research should be undertaken as a matterof high priority to determine whether ingestion of soy-based infant formulaecarries any risk for infants.
Table 4 shows a summary of exposure status of highly emphasized 7 kindsof EDCs with their regulation levels. In detail, these EDCs have the followingcharacteristics; exposure sources, exposure episodes, data of biological moni-toring and the gaps between exposure and regulation levels.
HEALTH RISKS OF EDCs
Mechanisms of EDCsEDCs may work following endocrine disrupting mechanisms (Figure 9).
The known endocrine disrupting mechanisms include: 1. aromatase inhibitor,2. estrogen receptor (ER) agonist/antagonist, 3. androgen receptor (AR)- ag-onist/antagonist, 4. arylhydrocarbon receptor (AhR) agonist, 5. interactions
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Endocrine Disrupting Chemicals 199
Figure 8: Comparison of estimated dietary isoflavone intakes for Western and Easternpopulations (mg isoflavone aglucone/day) (60); aUSA, Japanese-American.
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Tab
le4:
Exp
osu
reso
urc
ea
nd
leve
lof
EDC
sw
ithre
gu
latio
nle
vels.
EDC
sEx
po
sure
sour
ce
sEs
tima
ted
exp
osu
rele
vels
TDIa
orR
fDb
PC
Bs/
Dio
xin
s•
Ma
inly
tho
ug
hfo
od
se
spe
cia
llym
ilk(b
rea
sta
nd
da
iry),
fish
,a
nd
oth
er
me
ats
•O
cc
up
atio
na
lexp
osu
reo
cc
urs
ma
inly
via
the
inh
ala
tion
an
dd
erm
alr
ou
tes
(9).
•D
ioxi
nsc
inta
kein
Jap
an
(25)
(pg
TEQ
/kg
bw
/da
y):
1.49
in20
02(
0.52
an
d0.
97fo
rP
CD
D/F
sa
nd
PC
Bs,
resp
ec
tive
ly)
•D
ioxi
ns
inta
kein
Ge
rma
n(1
2)(p
gTE
Q/k
gb
w/d
ay)
:A
pp
roxi
ma
tely
2in
the
late
1980
sA
pp
roxi
ma
tely
1in
1994
-199
5
TDI:
2p
gTE
Q/k
gb
w/d
ay
(21)
•(E
SCSF
d)
DD
T/D
DE
•M
ain
lyth
ou
gh
foo
ds,
e.g
.,le
afy
an
dro
ot
veg
eta
ble
s,fa
rmm
ea
t,fis
ha
nd
po
ultr
y•
Oc
cu
pa
tion
ale
xpo
sure
sth
rou
gh
inh
ala
tion
an
dd
erm
alc
on
tac
t(9
).
•To
talD
DT
inta
kein
Jap
an
(25)
(µg
/kg
bw
/da
y):
0.00
6•
TDI:
0.5
µg
/kg
bw
/da
y(2
5)(U
SEPA
e,R
IVM
f )
Bisp
he
no
l•
Lea
ch
ing
of
the
ch
em
ica
lfro
mc
an
s,p
last
icb
ott
les
an
dd
en
talp
rod
uc
ts(9
).•
Bisp
he
no
lAin
take
(41-
42)
(µg
/kg
bw
/da
y):
1.2
inJa
pa
na
nd
1.6
inU
SA
•TD
I:10
µg
/kg
bw
/da
y(3
9–43
)(E
SCSF
d)
•R
fD:
50µ
g/k
gb
w/d
ay
(USE
PAe )
Ph
tha
late
s•
DEP
:d
erm
ala
nd
inh
ala
tive
exp
osu
res
•D
EHP
:o
rale
xpo
sure
s(4
9).
•D
EHP
inta
ke(4
4,51
)(µ
g/k
gb
w/d
ay)
:3–
30P
art
icu
larly
8.9–
9.1
(infa
nt)
,19
(to
dd
ler)
,14
(ch
ild),
8.2
(te
en
),5.
8(a
du
lt)in
Ca
na
da
•TD
I:37
µg
/kg
bw
/da
yfo
rD
EHP
(ESC
SFd)
•R
fD:
20µ
g/k
gb
w/d
ay
for
DEH
P(U
SEPA
e )(4
5)A
lkyl
-p
he
no
ls•
Foo
da
nd
wa
ter
fro
mfie
lds
spre
ad
with
sew
ag
eslu
dg
ec
on
tain
ing
alk
ylp
he
no
ls•
Foo
ds
with
ase
ptic
pa
cki
ng
•O
cc
up
atio
na
lexp
osu
res
thro
ug
hin
ha
latio
na
nd
de
rma
lco
nta
ct
(9).
•N
Pin
take
inG
erm
an
(53)
(µg
/da
y):
Ad
ult,
Bre
ast
milk
fed
infa
nt
an
dfo
rmu
lafe
din
fan
ts,
7.5,
0.2
an
d1.
4,re
spe
ctiv
ely
•TD
I:5
µg
/kg
bw
/da
yfo
rN
P•
13µ
g/k
gb
w/d
ay
for
NP
E(7
0)
Ph
yto
-e
stro
ge
ns
•M
ain
lyth
ou
gh
foo
ds
(60)
•Is
ofla
von
e:
leg
um
es,
len
tils,
soyb
ea
n•
Co
um
est
an
s:
you
ng
spro
utin
gle
gu
me
s•
Lig
na
ns
:c
ere
als,
linse
ed
,fr
uit
an
dve
ge
tab
les
•Is
ofla
von
ein
take
s(6
0)(m
giso
flavo
ne
ag
luc
on
e/d
ay)
:0.
76(U
SA),
1.6
(UK
),14
.88
(Ko
rea
),17
(Au
stra
lia),
25.4
(Ch
ina
),61
.4(S
ing
ap
ore
),70
(Ja
pa
n).
aTD
I,To
lera
ble
da
ilyin
take
;bR
fD,r
efe
ren
ce
do
se;c D
ioxi
ns,
PC
DD
s,P
CD
Fsa
nd
co
pla
na
r-P
CBs
;dES
CSF
,Eu
rop
ea
nC
om
miss
ion
Scie
ntifi
cC
om
mit-
tee
on
Foo
d;
e USE
PA,
U.S
.En
viro
nm
en
talP
rote
ctio
nA
ge
nc
y;f R
IVM
,N
atio
na
lIn
stitu
teo
fP
ub
licH
ea
ltha
nd
the
Envi
ron
me
nt,
the
Ne
the
rlan
ds.
200
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Endocrine Disrupting Chemicals 201
Figure 9: Potential mechanisms of endocrine disruption by EDCs (82).
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202 M. Yang et al.
Figure 10: Involvement of aromatase for estrogen biosynthesis.
with binding proteins, and 6. involvement in hormone-metabolism. In addi-tion, EDCs can work through combinations of the above mechanisms and inter-rupt cross talks between hormones to induce various kinds of endocrine-relateddisorders.
1. Aromatase InhibitorThe last step of the biosynthetic sequence of estrogen introduces an aro-
matic ring into the steroid molecule. The enzyme involved in this pathway isknown as aromatase (Figure 10) (71). Therefore, interferences with the catalyticactivity or expression of aromatase activity is expected to result in disruptionsof endocrine-regulated processes, such as estrous cycle, sperm production andmaturation, development of puberty, masculinization/feminization of sexualbehavior, and the inhibition or stimulation of the development and growthof hormone-dependent tumors of the breast, ovary, and prostate (72). Severalclasses of (relatively) persistent pesticides, such as organotin compounds, suchas tributyltin (TBT), DDT and several metabolites, a number of azole fungi-cides, and several 2-chloro- s- triazine herbicides, are suspected or have beenshown to interfere with steroidogenesis due to their aromatase inhibition.
2. Estrogen Receptor (ER)–Agonist/AntagonistThe action of oestrogen affects the bone, the cardiovascular system, the
brain, skin and many other peripheral tissues in both men and women (71).The main mode of action of EDCs is interactions with estrogen receptors (ERs).The ability of pesticides to act as estrogen agonists, inducing a uterotrophicresponse, has been known for over 30 years, and the estrogenicity of anthro-pogenic chemicals, for example, bisphenol A and DES, were first described in1938 (73). On the other hand, antiestrogens are estrogen receptor antagonists:they block or interfere with the estrogen receptor. Dioxins and some hydroxy-PCB congeners have reported anti-estrogenic effects (74).
3. Androgen Receptor (AR)–Agonist/AntagonistAndrogens are pivotal regulators of prostate cell growth, differentiations
and function, and their actions may be involved in prostate cancer development
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Endocrine Disrupting Chemicals 203
(75). Androgen-active EDCs include vinclozolin, DDE and trenbolone acetate(76).
On the other hand, vinclozolin and DDE have also antiandrogenic effectslike certain phthalates and certain other PCBs (77). Antiandrogenic alterationsmay bring out the demasculinization and feminization of male offspring, andthe masculinization and defeminization of female offspring (78).
4. Aryl Hydrocarbon Receptor (AhR)–AgonistDioxin and related pollutants trigger a marked morphological change
in epithelial cells that remodel their cytoskeleton to increase interactionwith extra cellular matrix while loosening cell–cell contacts. These dioxin-mediated effects are mimicked by constitutive expression and activation ofthe intracellular dioxin receptor (aryl hydrocarbon receptor, AhR) (79). Sev-eral studies have shown that the AhR bind TCDDs and several isostericpolychlorinated biphenyls (PCBs). After receptor-binding, the AhR signalingtranscription pathway is able to interact with multiple signal transductionpathways and induce or inhibit a variety of gene products (73).
5. Interactions with Binding ProteinsIt is known that the availability of internal and external estrogenic signals
to target tissues are modulated by extracellular binding proteins in the plasma.Estradiol and synthetic estrogen, diethylstilbestrol (DES) both bind to theestrogen receptors, and they also interact with serum transport proteins suchas α-fetoprotein, sex hormone binding globulin (SHBG), and albumin. Affini-ties of estradiol and DES to the transport proteins are of a different order ofmagnitudes (80).
In humans and some other mammals, the sex steroids testosterone and E2circulate in the bloodstream bound to SHBG and are thus not freely availableto target cells. Variation in the levels of SHBG (produced by the liver) will alterthe biological activity of testosterone and E2 without altering their production.
The main (stimulatory) regulators of SHBG production are the sex steroidsthemselves as well as other important regulators of SHBG production that arecomponents of other endocrine systems (73).
6. Involvement in Hormone-MetabolismEnvironmental chemicals with the potential to alter endogenous hor-
mone production or metabolism may pose a greater risk than do the manyweak, receptor mediated endocrine disruptor agents. For example, PCBs andpolycyclic aromatic hydrocarbons (PAHs), products of combustion, are potentsulphotransferase-1, which sulphates oestradiol before it is excreted. Such sup-pression can prolong the action of oestrogen (Figure 9), a change relevant tobreast cancer (81).
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204 M. Yang et al.
Immune and Hormonal Disorders
1. Immune AlterationsFor the PCBs, PCDFs, and PCDDs, the toxicity to the thymus, as for most
other target organs, appears mediated through AhR binding, resulting in likelyeffects on thymic hormones (73).
Victims of PCB-contaminated edible oil showed that levels of IgA and IgMin the serum are decreased. In addition, the PCB- contaminated oil inducedsuppression of cellular immunity such as delayed type skin response (82). Inaddition, the people exposed to TCDD-containing waste oils, in Missouri, USA,in 1971, showed immune alterations: an indication of an increased prevalenceof T4/T8-cell ratios less than 1.0 in the high-risk group (83). A study in workers,17 years after accidental exposure to TCDD, showed that the number of naturalkiller cells identified by the monoclonal antibody Leu-7 was significantly higherin the blood of TCDD-exposed workers in comparison to matched controls (84).
Concerning exposure to TCDDs and PCBs, Elo et al. reported decreasednumbers of T cells in peripheral blood, 5 weeks after the accidental exposure,and this status was recovered in four out of seven cases to normal values 7 weekslater. Lowered T-helper/T-suppressor cell ratios were also observed. During the7 months after the accident, nine out of the fifteen persons had at least oneupper respiratory infection (85).
Tonn et al. examined the effects of TCDD in 11 industrial workers whowere exposed to high doses of TCDD between 2 and 11 years before 1976 inGermany (86). Current TCDD body burdens were still at least 10 times higherin these exposed persons than in the average population. The TCDD-exposedpeople showed a reduced response to human lymphocyte antigen-a1llogeneiclymphocytes and interleukin-2-boosted proliferation. Furthermore, the capac-ity of a pool of T-cells isolated from TCDD-exposed subjects was to proliferateupon interleukin-2 stimulation significantly diminished (p ≤ 0.05). Therefore,TCDD is thought to have a long-term immunosuppressive effect on T-helpercell function.
2. DiabetesDioxin exposure has been known to induce adult-diabetes. In the Seveso
accident, deaths from diabetes were elevated among women in high exposurezones (RR ,1.7; 95% CI 1.1–2.7) (87). Exposure to high levels of Agent Orange,the widely used defoliant in the Vietnam War, is associated with a slight in-crease in the incidence of a form of leukemia (88). As compared to a controlgroup, 50% of the veterans with the highest exposures of Agent Orange in theVietnam were found to be likely to develop adult-onset diabetes (89).
The 1999 NIOSH study (90) reported an elevated incidence of Type 2diabetes in individuals who had high levels of serum dioxin relative to others.
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Endocrine Disrupting Chemicals 205
Finally, the ‘Veterans and Agent Orange/TCDD’ issue concluded that animal,laboratory, and human studies constitute reasonable evidence that TCDD ex-posure could affect Type 2 diabetes risk in humans by the National Academy ofSciences, USA, based on Longnecker et al. (91) and Cranmer et al. (92)’s reports.The conclusion put Type 2 diabetes onto the list of compensation due to AgentOrange.
3. Precocious PubertyPrecocious puberty is a condition where pubertal changes occur at an age
earlier than expected. Pubertal development is regulated by gonadotrophinsand sex hormones (73). In developing countries, puberal signs were observedfollowing increased exposure to xenoestrogens such as plastics or insecticides(93). For example, plasma of girls with precocious puberty was screened for pes-ticides and showed an increase p,p′-DDE in non-native children with precociouspuberty immigrating from developing countries to Belgium, compared withnondetectable levels in Belgian-born girls (94). Therefore, these results suggesta possible relationship to early exposure to p,p′-DDE in developing countries.
Both PCBs and DDT have been implicated as endocrine disrupters withpotential effects on the reproductive system and menstrual cycle. Cooperet al. investigated the effects of organochlorine exposure on the age ofnatural menopause (95). As a result, higher body burdens of DDE were as-sociated with earlier onset of natural menopause, however, PCBs were not.
Other studies showed that low birth weight was associated with earlymenarche, suggesting that intrauterine growth restriction affects the timingof pubertal development (96). For example, longitudinal clinical assessment of54 Spanish Catalan girls, followed from early onset of puberty, onset of breastdevelopment between 8.0 and 9.0 years of age, to final height. As a result, nor-mal and low birth weight girls had similar target heights and characteristics atdiagnosis of early puberty. However, menarche occurred on average 1.6 yearsearlier in low birth weight girls, and final height was >5 cm shorter in lowbirth weight girls compared to normal birth weight girls. The timing of menar-che and the level of final height in Catalan girls with early onset of pubertywere found to depend on prenatal growth. However, Gladen et al. reported thatlactational exposure to PCBs and DDE in U.S. children born was not signifi-cantly associated with changes in body proportions or maturation at 12 yearsof age (97).
Another reported EDC-induced hormonal disorder is thyroid dysfunction. Atotal of 13 epidemiologic studies between PCBs and thyroid status in humansfulfilled the inclusion criteria for a review (98). As a result, the overall im-pression is a lack of consistency between PCB studies of reported correlations,neither are there any obvious interstudy dose-response associations. Intrinsiclimitations of the cross-sectional epidemiologic studies used were indicated.
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206 M. Yang et al.
Reproductive Disorder
1. Polycystic Ovary SyndromeEDC-induced growth hormone-insufficient states in girls may disrupt ovar-
ian function, causing problems in sexual maturation, the menstrual cycle,and the reproductive ability of the female. Particularly, the polycystic ovarysyndrome (PCOS) is usually associated with the onset of puberty. The mensesmay at first be ovulatory, but shortly thereafter oligomenorrhea or amenorrheaensues (73). For example, Takeuchi et al. reported that the women with PCOShad higher serum bisphenol A than normal women without obesity. There was astrong relationship between serum bisphenol A and androgen levels, and theysuggest that the strong relationship is due to the effect of androgen on themetabolism of bisphenol A (99).
2. Sperm Counts and QualityReports of a global decrease in human sperm counts, coupled with hypothe-
ses linking these responses to environmental exposures, resulted in extensivenew scientific and regulatory initiatives (100). For example, Swan et al. sug-gested that sperm concentration and motility may be reduced in semi-rural andagricultural areas relative to more urban and less agriculturally exposed areaswith their current study (101).
Another study at the Massachusetts General Hospital reported that menwith higher phthalate levels have reduced sperm counts, lower sperm motilityand more deformed sperm (102). That is, men with higher mono-n-ethyl phtha-late were more likely to have lower sperm count, and men with higher MEPwere more likely to have lower sperm motility. These results demonstrate as-sociations between phthalate levels commonly experienced by the public andimpaired sperm quality.
3. Male Reproductive Tract AbnormalitiesBasic, clinical and epidemiological researches concerning adverse trends
in male reproductive tract health have made it evident that cryptorchidism,hypospadias may be interrelated with environmental factors, genetic defectsand polymorphism (103).
A number of epidemiological studies have suggested that exposure to pes-ticides may be linked to male reproductive tract abnormalities. For example,an increased risk of cryptorchidism and possibly hypospadias has also been re-ported in Norwegian boys born on farms where pesticides were being used (104).In addition, increases in urogenital defects have also been noted in children bornto those occupationally exposed to pesticides in Minnesota, USA (105). On theother hand, Pierik et al. (106) reported that paternal pesticide exposure was as-sociated with cryptorchidism in offsprings (OR, 3.8; 95% CI, 1.1–13.4). Smoking
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Endocrine Disrupting Chemicals 207
by the father was associated with hypospadias (OR, 3.8; 95% CI, 1.8–8.2). Onthe other hand, maternal occupational, dietary, and lifestyle exposures werenot associated with either abnormality cryptorchidism or hypospadias; how-ever, there are controversial reports for that (107).
The possible role of the maternal diet in offspring hypospadias has recentlybeen reported. Mothers who were vegetarian in pregnancy had an adjusted ORof 4.99 (95% CI, 2.10–11.88) of giving birth to a boy with hypospadias, comparedwith omnivores who did not supplement their diet with iron (108). Therefore,these results support the possibility that phytoestrogens have a deleteriouseffect on the developing male reproductive system.
Concerning anogenital distance (AGD) and EDC exposure in humans, Swanet al. colleted data from 85 mother-son pairs (109). The mothers’ urine specieswere analyzed for several phthalate metabolites, and the infant boys, aged2–36 months, were examined for genital developmental characteristics, includ-ing AGD, which was standardized for weight to develop an anogenital index(AGI). Although they found no sign of frank genital malformations or dis-ease, they discovered an association between elevated concentrations of fourphthalate metabolites in the mothers and shorter-than-expected AGI in theinfants.
The entire process of reproductive development is exquisitely sensitiveto minute changes in levels of the sex hormones, particularly during cer-tain critical windows of development. For example, low circulating levels oftestosterone have been demonstrated during gestation weeks 6–14 in boyswith cryptorchidism (110). In a case of accidental TCDD exposure at Seveso,1976, hypospadias was correlated with TCDD exposure in boys born after theexplosion (111). As mentioned above, the risks of teratogenic toxicity includinghypospadias, cryptorchidism due to pesticides, phytoestrogen intake, and ph-thalate exposure are reported in many studies; therefore, the teratogenicity isone of the most possible health risks of EDCs.
4. Sex RatioSex ratio–the proportion of male to female live births–is very constant on
a worldwide basis, typically ranging from 102 to 108 male births for every100 female births (77). In recent years, however, a number of reports havesuggested that environmental and occupational exposures to EDCs may bealtering the sex ratio within given human populations (73, 112). Occupationalexposure to organochlorines has been suggested to alter the sex ratio. For exam-ple, a group of Swedish researchers analyzed blood and semen samples from149 fishermen to investigate whether exposure to the persistent organochlo-rine pollutants CB-153 (a PCB) and p, p′-DDE affected the proportion of Y- andX-chromosome-bearing sperm (112). They discovered that elevated exposurelevels of both chemicals were positively associated with a higher proportionof Y-chromosome sperm and concluded that their findings add to evidence that
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exposure to persistent organic pollutants may alter the offspring sex ratio, withthe higher proportion of Y-chromosome sperm likely to lead to a higher propor-tion of male births. However, declining male births were observed from 1970 to1990 in Canada and the United States, i.e., 2.2 male births and 1.0 male birthsper 1000 live births, respectively (113).
Further evidence that environmental exposures may influence sex ratiocomes from an epidemiological report of a population highly exposed to TCDDfrom a chemical plant explosion in Seveso. Between April 1977 and December1984, corresponding to one half-life of TCDD, there was a reduction in sex ratioamong those with the greatest exposures (48 girls and 26 boys). The effect wasgreatest among parents with the highest serum levels of TCDD (73). In addition,Mocarelli et al. reported that there is an increased probability of female birthswith increasing TCDD levels in the father’s serum (114); however, the mother’sserum TCDD levels and the age at conception of either the father or motherwere not predictors of the outcome.
5. AbortionsSavitz et al. illustrated the problems of association between pesticide expo-
sure and abortions (115). They analyzed the outcome of 3,984 pregnancies in1,898 couples of farmers in Ontario included in the 1986 Canadian AgricultureCensus. The man’s exposure to pesticide was based on his experience in a 3-month window of time before conception. As a result, an increased spontaneousabortion rate was associated with reported use of thiocarbamates, carbaryl, andunclassified pesticides.
The Ontario farm family health study was also designed to assess retro-spectively the potential adverse effects of exposure to pesticides on pregnancy.Information on the health and life style is approximately 2,000 farm couples(116). As a result, preconception exposure to phenoxy herbicides was weaklyassociated with the risk of spontaneous abortions at <20 weeks’ gestation (OR,1.1; 95% CI, 0.6–1.9). When the analyses were restricted to spontaneous abor-tions of <12 weeks, the risk was more than doubled (OR, 2.5; 95% CI, 1.0–6.4).
Wives of workers exposed to organochlorine pesticides have showed ele-vated risk of spontaneous abortions and stillbirth in India (117). There is alsoevidence that organochlorine and carbamate pesticides cross the placenta andpossibly cause fetal death (118). With respect to time for conception, an increaseof 10 µg/L of DDT in maternal serum was reported to reduce daughters’ proba-bilities of pregnancy by 32%, whereas the same increase in DDE concentrationsraised the probability by 16% (119).
PCBs and some organochlorine insecticides were also analyzed in the serumof 17 women with recent missed abortions, 7 women who experienced one or sev-eral missed abortions in their past, and 7 women with normal, second trimesterpregnancy (120). As a result, the mean of PCB serum level in women with recentmissed abortions had relatively high PCB serum levels compared to the control
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Endocrine Disrupting Chemicals 209
group (103.04 vs. 20.69 ppb, p < 0.001). The mean PCB serum level of theformer missed abortions group was also significantly different from that of thecontrol group (82.00 vs. 20.69 ppb, p < 0.001). However, there was no increase inthe number of abortions at the presumably PCB-exposed spots in Wisconsin orNew York, compared to controls (121, 122). Therefore the associations betweenabortions and exposure to PCBs or organochlorine pesticides can be moved bychanges in cut point; thus, further well organized studies are required withmonitoring biological or ambient exposure of EDC.
6. EndometriosisEndometriosis is an estrogen-dependent disease characterized by the pres-
ence of endometrial glands and stroma outside the uterine cavity. It is a commongynecologic disorder as well as a major cause of infertility (73).
Associations between endometriosis and exposure to PCBs or dioxins havebeen studied (123, 124). There were controversial results in associations be-tween dioxin exposure and endometriosis. A Japanese group reported evenlower levels of serum bisphenol A in the patients with complex endometrialhyperplasia with malignant potential than controls (125). Therefore, due to con-troversial reports, associations between risk of endometriosis and EDC shouldbe further studied.
Neurobehavioral DisordersNeurobehavioral functions may not be directly affected by chemicals but
result from chemical-induced morphological and/or functional alterations in avariety of neuroendocrine pathways (73). A potential variety of health risksinduced by EDCs can be motor impairment, mental impairment and memoryloss to subtle behavioral changes.
In the case of the Yusho accident, frequent symptoms in affected adultswere central and peripheral nervous system disorders including headache, lossof memory, and hypoesthesia or neuralgia of the limbs (73). After the accident,persistent growth retardation, movement disorders, generalized slowness, andsubstantially lower IQ (average IQ was around 70) were found in a subset ofchildren who were followed for several years. Patients of Yu-Cheng in Taiwanin 1979, a similar symptom with Yusho, showed a number of developmentalabnormalities, including lower body weight and height, higher activity levels,greater incidence of behavior problems, and lower IQ scores, were observed(126).
Hypotonia exhibited negative associations with PCBs in maternal plasmain a Dutch breast milk study (127): Psychomotor was delayed at 3 and 7 monthold babies in relation to PCBs in maternal plasma. The Dutch group also foundneuromuscular delays associated within utero exposure to PCBs in 3 month-oldbabies.
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The effect of prenatal exposure to background levels of PCBs and dioxinson infant neurodevelopment was elucidated in the Sapporo study (128). It wasstudied that the associations between the total or individual congener level ofPCBs and dioxins in 134 Japanese pregnant women’s peripheral blood and themental or motor development of their 6-month-old infants. The mean level ofTEQ was 18.8 (4.0–51.2) pg/g of lipids in the blood of 134 mothers. The total TEQvalue was shown not to be significantly associated with mental developmentalindex (MDI) or psychomotor developmental index (PDI). However, the levels ofone PCDD congener, total PCDDs, and total PCDDs/PCDFs were significantlynegatively associated with MDI. In addition, the levels of two PCDD congenersand three PCDF congeners were significantly negatively associated with thePDI.
Hypothyroidism may lead to retardation and other serious developmentaleffects via cross talks of endocrine. However, the role of thyroid hormones inbrain development is still not completely understood (129, 130). Haddow et al.(131) collected and stored blood from women in their second trimester of preg-nancy and revealed a possible association between relatively slight reductionin the amount of circulating free thyroid hormone levels in the mothers andretard in the intellectual development of their children. That is, the childrenwho had mothers with 9.1 ppt (geometric mean, GM) of free thyroxine (FT4)during gestation, scored 4 points higher in IQ than those with 7.5 ppt (GM) ofFT4 (p = 0.002).
In addition, hypothyroid alterations associated with neonatal PCBs/polyhalogenated aromatic hydrocarbons at background environmental levelsof exposure have been reported fairly consistently in developmental studies ininfants (73). For example, higher PCDD, PCDF, and PCB levels in human milkwere significantly correlated to lower plasma levels of maternal total triiodothy-ronine and total thyroxine, and to higher plasma-levels of TSH in the infants inthe 2nd wk and 3rd mo after birth in the Dutch breast milk study (132). In thecase of bisphenol A, it inhibits thyroid receptor (TR)-mediated transcription asan antagonist (133, 134). Therefore, there is some possibility that EDCs affectneurobehavioral disorders particularly through teratogenicity and alterationof thyroid hormone. In order to prove the possibility, more consistent and re-liable evidence, which are supported with mechanisms of endocrine disorders,are required.
In addition, various endocrine disorders, which are simultaneously inducedby EDCs, are expected due to cross talk between endocrines. However, we couldnot observe any significant association between bisphenol A- exposure levelsand mild endocrine disorder syndromes such as thirst/frequent urination, dizzi-ness, heat prostration, sweating, bruising, hot flushes, and swelling of lymphnodes in our recent Korean study (135). Therefore, these kind approachesare needed with various combined health outcome, based on endocrine-crosstalks.
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Endocrine Disrupting Chemicals 211
Health Risks Related to PhytoestrogensPhytoestrogens represent a family of plant compounds that have been
shown to have both estrogenic and antiestrogenic properties. Accumulatingevidence suggest that phytoestrogens may be beneficial to cardiovascular dis-eases, cancer, osteoporosis, and menopausal symptoms (136).
A population based case control study examined the association betweensoy food intake and breast cancer risk among women in Shanghai (137). Thestudy included 1459 breast cancer cases and 1556 age matched controls. Aborderline reduction in risk was observed among women who reported eatingsoy foods at least once per week (OR, 0.78; 95% CI, 0.52–1.16). In addition,high consumption of soy products and other legumes showed a decreased risk ofendometrial cancer (OR, 0.46; 95% CI, 0.26–0.83). Similar reductions in the riskof the endometrial cancer were found for increased consumption of other sourcesof phytoestrogens, such as whole grains, vegetables, fruits, and seaweeds. Thesedietary associations may explain in part the reduced rates of uterine cancer inAsian countries compared with those in the United States (138).
Another case-control study investigated whether certain dietary factors hadan etiological association with ovarian cancer in China (254 cases; 652 controls)(139). As a result, there was a significant inverse association between soybeanproducts and risk of ovarian cancer.
In the case of prostate cancer, a prospective study was conducted to inves-tigate effects of soy intake on prostate cancer with 225 incident cases in 12,395California Seventh-Day Adventist men who stated how often they drank soymilk (140). As a result, frequent consumption—more than once a day—of soymilk was associated with 70% reduction of the risk of prostate cancer (RR, 0.3;95% CI, 0.1–1.0).
Thyroid function during early pregnancy is an important determinant ofearly fetal brain development (141). It has been suggested that feeding prac-tices in infancy may affect the development of various autoimmune diseaseslater in life. Fort et al. obtained a detailed history of feeding practices in 59children with autoimmune thyroid disease, their 76 healthy siblings, and 54healthy non-related control children (142). As a result, there was no differencein the frequency and duration of breast milk feeding in early life among thethree groups of children. However, the frequency of feedings with soy-based milkformulas in early life was significantly higher in children with autoimmune thy-roid disease as compared with their siblings (p < 0.01) and healthy non-relatedcontrol children (p < 0.02). Therefore, this retrospective analysis documents theassociation of soy formula feedings in infancy and autoimmune thyroid disease.
Previously mentioned at the male reproductive tract abnormalities, vege-tarianism and consumption of phytoestrogens in maternal diet were reported toincrease hypospadias (108). Therefore, this result supports the possibility thatphytoestrogens have a deleterious effect on the developing male reproductivesystem.
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Health Risks Related to Tobacco and Metals as EDCsTobacco smoking is a source of mixed EDCs, e.g., pesticides, PAHs, cad-
mium, etc. It has been hypothesized that smoking during pregnancy couldincrease the offspring’s risk for testicular cancer. To clarify the associationbetween smoking during pregnancy and testicular cancer, Kaijser et al. stud-ied cancer risk among offspring of women diagnosed with lung cancer (143).Through the use of the Swedish Cancer Register and the Swedish Second-Generation Register, they identified 12,592 male offspring of mothers with asubsequent diagnosis of lung cancer. OR for the testicular cancer in offspringof smoker-mothers was approximately 2-fold higher than those of nonsmokermothers (OR, 1.90; 95% CI, 1.35–2.58). This result supports the hypothesis thatexposure to cigarette smoking in utero increases the risk of testicular cancer.
Numerous studies have investigated the incidence of cancer among childrenof women who smoked during pregnancy (144). Associations of the maternalsmoking and acute lymphocytic leukemia and lymphoma have been confirmedin several studies (144, 145), however, the NIH group concluded that maternalsmoking during pregnancy is not associated with an increased risk of childhoodcancer (146).
Several case-control studies support a positive association betweencigarette smoking and ovarian cancer. In most of these studies, the availableevidence suggests an affirmative association between smoking and certainmucinous types of tumors. That is, long-term cigarette smoking was associatedwith an increased risk of epithelial ovarian tumors, with women who hadsmoked for years being at the highest risk (RR, 2.5; 95% CI,1.37–4.56), ascompared with women who had never smoked (147). Another population-basedcase-control study suggested that smoking is a risk factor for ovarian can-cer, particularly mucinous and borderline mucinous lesions, among currentsmokers (OR, 1.4; 95% CI, 0.7–2.9) and former smokers (OR, 2.5; 95% CI,1.1–5.4) (148). (There is evidence indicating that smoking may play a role inthe development of some types (mucinous) of ovarian cancer and not all types).Therefore, long term and mixed exposure of EDCs such as smoking should notbe ignored for prevention of EDC-related cancer.
Metal ions may be capable of interfering with oestrogen action, so defininga class of inorganic xenoestrogens now termed metalloestrogens (149). Martinet al. provided evidence that cadmium acted as an estrogen mimic that canadversely affect estrogen-responsive tissues such as the uterus and mammaryglands (150).
Cadmium is only one constituent of tobacco smoke, however, smoking doesincrease body cadmium burden (151). Reported associations between cadmiumand breast cancer suggest an ability to mimic oestrogen action of cadmium forbreast cancer (152).
Table 5 summarizes mechanisms of endocrine disruption in the highlyemphasized EDCs and health risks. The health risks are classified into
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Tab
le5:
End
oc
rine
disr
up
ting
me
ch
an
isms
of
EDC
sa
nd
he
alth
risks
.
Hea
lthris
ks
EDC
sM
ec
hani
sms
Imm
une
and
horm
ona
ldis
ord
ers
Rep
rod
uctiv
ed
iso
rde
rsN
euro
be
havi
ora
ldis
ord
ers
PC
Bs•
ERa
nta
go
nist
(74)
•A
Ra
nta
go
nist
(77)
•A
hR
ag
on
ist(7
9)•
Invo
lve
me
nt
of
me
tab
olis
m(8
1)
•Th
yro
idd
ysfu
nc
tion
±(9
8,15
8)•
Imm
un
esy
ste
m±
(73,
82,8
5)•
Pre
co
scio
us
pu
be
rty
±(9
5)
•En
do
me
trio
sis−
(123
)•
Spe
rmc
ou
nts
/qu
alit
y±
(155
)•
Ab
ort
ion
+(1
20–1
22)
•Bi
rth
size
−(1
56–1
57)
•Se
xra
tio−
(112
)
•G
en
de
rd
ep
en
de
nt
be
ha
vio
r−
(157
)•
Ne
uro
be
ha
vio
ral
dys
fun
ctio
n±
(126
–128
,13
2,15
9)
Dio
xin
•ER
an
tag
on
ist(7
4)•
Ah
Ra
go
nist
(79)
•Th
yro
idd
ysfu
nc
tion
+(1
54,1
58)
•Im
mu
ne
syst
em
±(8
2–84
,86
)•
Dia
be
tes
+(8
7–92
)
•En
do
me
trio
sis±
(124
)•
Sex
ratio
±(1
14)
•A
bo
rtio
n±
•H
ypo
spa
dia
s+
(111
)
•M
en
tala
nd
psy
ch
om
oto
rfu
nc
tion
−(1
28)
DD
T/D
DE
•A
rom
ata
sein
hib
itor
(72)
•A
Ra
go
nist
/an
tag
on
ist(7
6)•
AR
-an
tag
on
ist(7
7)
•P
rec
oc
iou
sp
ub
ert
y±
(93,
95)
•Im
mu
ne
syst
em
±•
Sex
ratio
−(1
12)
•A
bo
rtio
n±
(115
–117
,119
,120
)•
Spe
rmc
ou
nt/
qu
alit
y±
(104
,105
,155
)
•M
en
tala
nd
psy
ch
om
oto
rfu
nc
tion
±(1
59–1
60)
BPA
•ER
ag
on
ist(7
3)•
Pre
co
cio
us
pu
be
rty
+(9
9)•
Dia
be
tes
±(1
62)
•En
do
me
trio
sis+
(125
)•
PC
OS
+(9
9)•
Bra
ind
am
ag
e±
(133
–134
)P
hth
ala
te•
AR
-an
tag
on
ist(7
7)•
ER-a
go
nist
(73)
•P
rec
oc
iou
sp
ub
ert
y+
(164
)•
AG
I+(1
09)
•Sp
erm
mo
tility
+(1
77)
•R
ep
rod
uc
tive
syst
em
±(1
63)
Ph
yto
-e
stro
ge
n•
ERa
nta
go
nist
(153
)•
ERa
go
nist
(153
)•
Me
nst
rua
lcyc
le±
(138
)•
Thyr
oid
dys
fun
ctio
n−
(142
)•
Imm
un
esy
ste
m±
(142
)•
Sex-
ho
rmo
ne
co
nc
en
tra
tion
±(1
61)
•H
ypo
spa
dia
s+
(108
)•
End
om
etr
iosis
±(1
38)
PAH
sin
tob
ac
co
•In
volv
em
en
to
fm
eta
bo
lism
(81)
•P
rec
oc
iou
sp
ub
ert
y+
(170
)•
Ab
ort
ion
+(1
65–1
66)
•G
en
itala
bn
orm
alit
y+
(168
)•
Birt
hw
eig
ht
−(1
66)
•In
telle
ctu
alf
un
ctio
n−
(166
–167
)
DES
•ER
ag
on
ist(7
3)•
Inte
rac
tion
bin
din
gp
rote
ins
(80)
•P
rec
oc
iou
sp
ub
ert
y+
(175
)•
Imm
un
esy
ste
m±
(173
–174
)•
Ab
ort
ion
+(1
70–1
71)
•M
ale
rep
rod
uc
tive
syst
em
±(1
72,1
76)
•Sp
erm
co
un
t/q
ua
lity
±(1
76)
•P
syc
ho
sexu
alf
un
ctio
n−
(171
)
+,a
sso
cia
ted
;−,
no
ta
sso
cia
ted
;±,
ass
oc
iate
do
rn
ot.
213
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214 M. Yang et al.
3 categories, i.e., 1. immune and hormonal, 2. reproductive, and 3. neurobehav-ioral disorders.
CONCLUSIONS
Exposure monitoring for EDCs in lifestyle has not been performed extensivelyenough. Considering toxicity of EDCs such as teratogenicity, exposure or bi-ological monitorings of EDCs are particularly required for highly susceptiblepeople, i.e., immature infants and children, who are undergoing sexual devel-opment and growth. In addition, pregnant women and the fetus, breast-fedchildren, vegetarians and women in menopause should be considered as EDC-high susceptible population.
In the case of EDCs health risks, the problems researchers met are thatEDCs responses in human are not clearly clarified through experimental andepidemiological researches. Therefore, researches have made efforts to findmissed or masked health effects by EDCs. One of these efforts is that the EDC-influenced spectrum recently became broader, including thyroid disorder andmental retardation, immune disorders and sick building syndrome or multi-chemical sensitivity.
Based on establishing and understanding various action-mechanisms andscreening methods of EDCs, further well organized epidemiological studies forEDCs and health risks are required and they will provide constant responseagainst EDCs.
Therefore, considering particular status of EDC-endpoints, we suggest thatone of the best ways to prevent unknown health risks from EDCs is to performcontinuous EDC-exposure monitoring or to do surveillance for EDC-release intothe environment.
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