Developmental Neurotoxicants in E-Waste: An Emerging Health Concern

Objective Electronic waste (e-waste) has been an emerging environmental health issue in both developed and developing countries, but its current management practice may result in unintended developmental neurotoxicity in vulnerable populations. To provide updated information about the scope of the issue, presence of known and suspected neurotoxicants, toxicologic mechanisms, and current data gaps, we conducted this literature review. Data sources We reviewed original articles and review papers in PubMed and Web of Science regarding e-waste toxicants and their potential developmental neurotoxicity. We also searched published reports of intergovernmental and governmental agencies and nongovernmental organizations on e-waste production and management practice. Data extraction We focused on the potential exposure to e-waste toxicants in vulnerable populations—that is, pregnant women and developing children—and neurodevelopmental outcomes. In addition, we summarize experimental evidence of developmental neurotoxicity and mechanisms. Data synthesis In developing countries where most informal and primitive e-waste recycling occurs, environmental exposure to lead, cadmium, chromium, polybrominated diphenyl ethers, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons is prevalent at high concentrations in pregnant women and young children. Developmental neurotoxicity is a serious concern in these regions, but human studies of adverse effects and potential mechanisms are scarce. The unprecedented mixture of exposure to heavy metals and persistent organic pollutants warrants further studies and necessitates effective pollution control measures. Conclusions Pregnant women and young children living close to informal e-waste recycling sites are at risk of possible perturbations of fetus and child neurodevelopment.


Review
Electronic waste (ewaste) has emerged as a critical global environmental health issue because of its massive production volume and insufficient management policy in many countries (Ogunseitan et al. 2009). Ewaste includes waste cathode ray tube (CRT) tele visions, desktops, laptops, CRT monitors, liquid crystal display (LCD) monitors, cell phones, keyboards, computer mice, print ers, and copiers. Ewaste contains metals and persistent organic pollutants (POPs); inap propriate recycling processes occur in sev eral developing countries and result in the release of these toxicants into the environ ment (LaDou and Lovegrove 2008; Robinson 2009). Although serious health concerns arise from these primitive recycling activities, the research needs are largely unaddressed. The developing fetus and child are particularly vulnerable to several known and suspected developmental neurotoxicants in ewaste.
In this review, we survey the literature to provide updated information about major toxi cants in ewaste, potential neuro developmental toxicity in children, and potential preventa tive measures to reduce exposure. Because the rate of ewaste accumulation is startling and the combinatorial effects of toxicants are com plex, this review addresses an urgent need to evaluate potential adverse health effects of this unprecedented exposure scenario.

Production and Management of E-Waste
Ewaste is the fastestgrowing stream of municipal solid waste, but its management is a significant environmental health con cern. It is estimated that 20-50 million tons of ewaste are produced annually worldwide; the United States, Western Europe, China, Japan, and Australia are the major produc ers [Cobbing 2008;Davis and Herat 2010;Robinson 2009; United Nations Environment Programme (UNEP) 2005]. Figure 1 shows an incomplete list of ewaste volume and major informal recycling sites. According to a U.S. Environmental Protection Agency (EPA) estimate, the United States generated approxi mately 2.5 million tons of ewaste in 2007, which accounts for about 2% of municipal solid waste and has a projected annual increase of 3-5% (U.S. EPA 2008). In the United States, only about 18% of ewaste is collected for recycling, with the remaining 80% sent to landfill and 2% for incineration (U.S. EPA 2007(U.S. EPA , 2008. Landfill can cause metal leaching from the ewaste (Dagan et al. 2007). Burning ewaste may produce extremely toxic dioxins and furans (Li et al. 2007). Environmentally friendly recycling has not been widely used, although it is a promising approach to tackle the ewaste problem (UNEP 2009). The European Union has enacted two directives to address the increasing concerns on ewaste: the Restriction on the Use of Hazardous Substances (RoHS) and the Waste Electrical and Electronic Equipment (WEEE) (European Union 1995, 1996LaDou and Lovegrove 2008;Ogunseitan et al. 2009). The RoHS directive restricts the use of lead (Pb), cad mium (Cd), mercury (Hg), hexavalent chro mium [Cr(VI)], polybrominated biphenyls, and polybrominated diphenyl ethers (PBDEs) in new electronic devices. The WEEE directive requires the manufacturers to take responsibil ity for collecting and recycling ("takeback") of the ewaste. In contrast, the United States does not have legally enforceable federal poli cies to regulate ewaste despite a patchwork of legislation in about 25 states (e.g., mandating statewide ewaste recycling or banning land fill disposal of CRT monitors) [Electronics Take Back Coalition (ETBC) 2010; LaDou and Lovegrove 2008; Ogunseitan et al. 2009]. These include most coastal states, the Great Lakes states, Oklahoma, and Texas. Japan has an existing recycling system for limited home electrical appliances, but it does not cover all ewaste, and illegal dumping and transfer still occur (Aizawa et al. 2008;LaDou and Lovegrove 2008).
Although the Basel Convention regulates transboundary movement of hazardous waste, significant amounts of ewaste have been exported to developing countries and recycled in local towns and villages, using primitive technologies (LaDou and Lovegrove 2008). In the biomedical literature, primitive recycling of ewaste occurs in Guiyu, Taizhou, and Jinghai, China (Huo et al. 2007;Wong et al. 2007), Bengaluru and Dehli, India (Chatterjee 2008;Ha et al. 2009), Lagos, Nigeria (Osibanjo and Nnorom 2007;Schmidt 2006), andTrang Minh, Dong Mai, andBui Dau, Vietnam (Tue et al. 2010) (see also Figure 1). A recent report listed a few other countries that may have smallscale informal ewaste recycling (Brazil, Colombia, Kenya, Mexico, oBjective: Electronic waste (e-waste) has been an emerging environmental health issue in both developed and developing countries, but its current management practice may result in unintended developmental neurotoxicity in vulnerable populations. To provide updated information about the scope of the issue, presence of known and suspected neurotoxicants, toxicologic mechanisms, and current data gaps, we conducted this literature review. data sources: We reviewed original articles and review papers in PubMed and Web of Science regarding e-waste toxicants and their potential developmental neurotoxicity. We also searched published reports of intergovernmental and governmental agencies and nongovernmental organizations on e-waste production and management practice. data extraction: We focused on the potential exposure to e-waste toxicants in vulnerable populations-that is, pregnant women and developing children-and neurodevelopmental outcomes. In addition, we summarize experimental evidence of developmental neurotoxicity and mechanisms. data synthesis: In developing countries where most informal and primitive e-waste recycling occurs, environmental exposure to lead, cadmium, chromium, polybrominated diphenyl ethers, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons is prevalent at high concentrations in pregnant women and young children. Developmental neurotoxicity is a serious concern in these regions, but human studies of adverse effects and potential mechanisms are scarce. The unprecedented mixture of exposure to heavy metals and persistent organic pollutants warrants further studies and necessitates effective pollution control measures. conclusions: Pregnant women and young children living close to informal e-waste recycling sites are at risk of possible perturbations of fetus and child neurodevelopment. Morocco, Peru, Senegal, South Africa, and Uganda) (UNEP 2009). Developing countries are generating more and more ewaste in their own territories and may also feed the recy cling business (LaDou and Lovegrove 2008;Robinson 2009).The purpose of recycling activities in these developing countries is to recover gold, silver, copper, zinc, iron, tin, and other metals for profit (Huo et al. 2007;Wong et al. 2007). However, because of a lack of stringent environmental regulation and worker protection, toxicants in ewaste cause serious contaminations of local air, dust, soil, and water (Ogunseitan et al. 2009;Schmidt 2006;Wong et al. 2007). The environmen tal consequence is dire in these regions if the activities remain uncontrolled. Further, infor mal recycling processes (dismantling, cut ting, heating, acid leaching, and burning) in small town and village workshops expose the workers and residents to dangerous mixtures of metals and other pollutants (LaDou and Lovegrove 2008).

Developmental Neurotoxicants in E-Waste
Electronic devices consist of a large number of chemical elements and compounds. Even a cell phone can contain > 40 elements from the periodic table (UNEP 2009). The metals in ewaste include steel (iron), copper, alu minum, tin, Pb, nickel, silver, gold, arsenic, Cd, Cr, indium, Hg, ruthenium, selenium, vanadium, and zinc. The toxicity of these chemicals in ewaste remains to be deter mined. However, some chemicals are known or suspected to have developmental neuro toxicity. Neurodevelopmental deficits are a serious concern of exposure to ewaste toxi cants, because children living in ewaste recy cling communities may have been exposed to highlevel toxicant mixtures throughout their lifetime. Infants and young children have relatively smaller body weight than adults, but their toxicant body load can be higher because they have relatively low body weight [American Academy of Pediatrics (AAP) 2003]. Developing fetuses and young children are at critical windows of neuronal growth, differentiation, migration, synaptogenesis, and myelination. Disruption of these fine tuned processes in human neurodevelopment can have detrimental effects (Dietrich 2010). The commonly assessed neuro develop mental end points include intelligence quotient (IQ), memory, language, gross and fine motor skills, attention, executive functions, and behavior. Obviously, a focus on develop mental neuro toxicity in this review does not exclude the possibility of adverse effects on other organ systems, but many previous human studies of metal and POP exposure in community settings revealed deficits in neurological func tions in children (Dietrich 2010;Wright and Baccarelli 2007). Table 1 summarizes the developmental neurotoxicity and expo sure routes of common ewaste toxicants. In addition to exposure to ewaste, children are exposed to these toxicants from other existing sources (e.g., Pb and Hg from power plants and other industrial emissions as well as diet) (AAP 2003).
Lead. Pb is arguably the moststudied developmental neurotoxicant and unfor tunately is also one of the major toxicants in ewaste. An old CRT television contains about 1.5-2 kg Pb, and a CRT computer monitor contains about 0.5 kg Pb (U.S. EPA 2007EPA , 2008. Pb has also been used in solder in printed circuit boards and other compo nents (Ramesh et al. 2007). In 1 to 6year old children living in a primitive ewaste recycling site, the mean blood Pb level approaches 15 µg/dL, which is 50% higher than the neighboring control site (~ 10 µg/dL) (Huo et al. 2007;Zheng et al. 2008). Blood Pb levels ≥ 10 µg/dL in early childhood are detrimental to neurodevelopment, and the recognized adverse effects include impaired cognitive function, behavioral disturbances, Figure 1. Estimated annual production of e-waste and major recycling sites. Estimates are from Robinson (2009), Davis and Herat (2010), and Cobbing (2008) and may not reflect current production. In addition, the estimates are not complete for many regions, for example, Japan, Russia, and Canada. The number of recycling sites is by no means complete but may represent major processing regions of e-waste. Known major e-waste recycling sites attention deficits, hyperactivity, and conduct problems (Bellinger 2004). Newly identified neuroanatomical changes in young adults who are exposed to Pb in childhood include reduced gray matter in the prefrontal region and diffusivity changes in white matter that indicate effects on myelination and axonal integrity (Brubaker et al. 2009;Cecil et al. 2008). Childhood Pb exposure, especially earlyschoolage blood Pb levels, strongly predict neurologic deficits in children and young adults (Hornung et al. 2009). There is a considerable amount of evidence show ing that every 10µg/dL increase of blood Pb concentration is associated with a deficit of 2-3 IQ points (Pocock et al. 1994). Current research suggests that a blood Pb concentra tion < 10 µg/dL is also harmful for cogni tive function (Canfield et al. 2003;Lanphear et al. 2005). High Pb exposure in childhood has been associated with delinquent behav iors and criminal activities in adolescents and young adults (Needleman et al. 2002;Wright et al. 2008). In children, Pb exposure has also been associated with increased risk of atten tion deficit hyperactivity disorder (Braun et al. 2006). Ewaste exposure represents a situation of continuous exposure, which raises concerns about neurodevelopmental deficits in young children and across the lifespan.
Mercury. Because Hg is used in laptop monitors, cold cathode fluorescent lamps, cell phones, and printed circuit boards (e.g., switches, relays), improper recycling of ewaste may release Hg in its elemental vapor form into the environment (Ramesh et al. 2007). Each individual electronic device contains a very small amount of Hg (< 1-2 g) (U.S. EPA 2007), but intensive processing of millions of these devices could be highly problematic for the environment. In bodies of water, bac teria can transform inorganic Hg to organic form [i.e., methylmercury (MeHg)], and fish bio accumulate MeHg. Eating MeHg contaminated fish is the primary route of exposure in the general population, but people living in ewaste recycling sites may be exposed to both inorganic and organic Hg. So far, there is a lack of studies investigating Hg lev els in children who lived in ewaste recycling sites. Currently, there is considerable debate about neurodevelopmental effects of moder ate MeHg levels (maternal hair Hg 4-6 µg/g) or lowerlevel exposure because of conflicting results from the research in the Faroe Islands and Seychelles (Debes et al. 2006;Grandjean et al. 1997;Myers et al. 2009). The study in the Faroe Islands identified an association of prenatal MeHg exposure [geometric mean (GM) = 4 µg/g in maternal hair and 23 µg/L in cord blood] and deficits in motor function, attention, and verbal domains in children up to 14 years of age but did not find associations for postnatal exposure (GM = 3 µg/g in hair and 9 µg/L in blood at 7 years of age) (Debes et al. 2006). The research in Seychelles, how ever, did not find a consistent pattern of asso ciation between prenatal (mean = 7 µg/g in maternal hair) or postnatal MeHg (mean = 6 µg/g in hair at 9 years of age) and neuro develop mental end points (Davidson et al. 2010;Myers et al. 2009). An integrative analy sis of three cohorts (Faroe island, Seychelles, and another New Zealand study) found an overall child IQ change of -0.18 points [95% confidence interval (CI), -0.38 to -0.01] for each microgram per gram increase of maternal hair MeHg (Axelrad et al. 2007). A recent study of U.S. background level MeHg expo sure (~ 0.5 µg/L in whole blood at 2 years of age) did not reveal significant associa tions with neurodevelopmental outcomes in children at ages 2, 5, and 7 years (Cao et al. 2010). For Hg vapor exposure from dental amalgam, two recent large clinical trials did not find adverse effects on cognitive function in children (Bellinger et al. 2006;DeRouen et al. 2006). In some Asian coastal regions, the GM hair Hg levels can reach 1-2 µg/g in women of reproductive age . The exposure to Hg from ewaste recycling needs to be characterized in pregnant women and young children from ewaste recycling sites, and if elevated, the neurodevelopmental effects should be examined.
Cadmium. Cd is used in nickel-cadmium (NiCd) batteries, surface mount devices chip resistors, infrared detectors, and semiconduc tor chips (Ramesh et al. 2007). Lithiumion batteries have replaced NiCd batteries in many electronic devices, but ewaste still con tains old rechargeable batteries. Compared with Pb and Hg, the adverse neurodevelop mental effects of Cd are less well charac terized in children. Cd levels in hair have been asso ciated with deficits in cognition, learning, behavior, and neuromotor skills in children in earlier studies (Pihl and Parkes 1977;Thatcher et al. 1982), but inadequate control for Pb levels in the data analysis has been a concern. A recent study indicates that current background Cd exposure (~ 0.2 µg/L) in U.S. children may not cause significant cognitive and behavioral problems (Cao et al. 2009). In a Chinese birth cohort study, however, higher Cd exposure in cord blood (> 0.6 µg/L) was associated with a 4point FullScale IQ deficit at preschool age after adjustment for cord blood Pb levels (Tian et al. 2009). The pla centa limits the transfer of Cd from mother to fetus after the first trimester, but high cord blood Cd in infants may suggest high maternal exposure. These infants may also be postnatally exposed to Cd in the same mater nal living environment (Osman et al. 2000). Because the halflife of Cd in kidneys and bones is estimated to be 10-30 years (Jarup and Akesson 2009), caution should be exer cised to prevent Cd exposure in young chil dren. The average blood Cd levels in children from an ewaste recycling site in China was 1.6 µg/L, significantly higher than the con trol site (1.0 µg/L) (Zheng et al. 2008). In Asian countries where rice consumption and environmental tobacco smoke are more com mon, children already get higher Cd exposure than those in Western countries (Jarup and Akesson 2009). Living in an ewaste recy cling site substantially increases exposure of children to Cd, but the neurodevelopmental effects remain to be determined.
Hexavalent chromium. Cr(VI) is used in metal coatings of some electronic devices for corrosion protection. It is a known human carcinogen after occupational inha lation exposure, but its toxicity in fetuses and children after environmental exposure is largely unknown (Pellerin and Booker 2000). Epidemiologic study of Cr expo sure and child neurodevelopment is lacking. One animal study reported motor activity decrease in rats after chronic Cr exposure  (azMayans et al. 1986). Oxidative stress in hypothalamus and anterior pituitary has been reported in Crexposed animals (Nudler et al. 2009). Increased urinary 8hydroxy2´ deoxyguanosine, a biomarker for oxidative DNA lesions, was reported in children with high urinary Cr (Wong et al. 2005). Ewaste recycling can result in high Cr exposure in fetuses, with one report of mean cord blood Cr of 99 µg/L, significantly higher than the controlsite mean of 32 µg/L ).
The reported Cr levels were very high com pared with findings from a large U.K. study (serum ~ 0.5 µg/L) and Italian Cr workers (whole blood ~ 6.9 µg/L) (Davies et al. 1997;Minoia and Cavalleri 1988). PBDEs. PBDEs--a group of brominated flame retardants--are used in electronic prod ucts to reduce flammability. Animal studies of PBDEs strongly suggest increased risk of thyroid hormone disruption [PBDEs and thy roxine (T 4 ) are structurally similar], hyperactiv ity, cognitive deficits, and impaired memory (Costa and Giordano 2007). Susceptibility of children to PBDEs is a major concern, because children often have two to three times higher serum concentrations than their parents (Toms et al. 2009). A recent publication of prenatal exposures to PBDEs and FullScale IQ deficits [four points by interquartile range of BDE47 (20 ng/g lipid)] in preschool children raised the concern of neurodevelopmental consequences (Herbstman et al. 2010). This association needs to be confirmed in other cohort studies. Median serum ΣBDEs (BDE209 included) of up to 600 ng/g lipid were detected in recy cling workers ), but most stud ies found a mean or median of 100-400 ng/g lipid in the sera of local residents in the recy cling sites Yuan et al. 2008;Zhao et al. 2010). Breast milk from lactat ing mothers in the recycling sites also contains high PBDEs, with reported ΣBDEs of 84 ng/g (BDE209 included) and 117 ng/g (BDE209 not included) lipid in two different small stud ies in Vietnam and China, respectively (Leung et al. 2010;Tue et al. 2010). In contrast, the median serum ΣBDEs in the U.S. general population is ~ 40-60 ng/g lipid (BDE209 not included), and that in Europe and Asia is usually < 10 ng/g lipid Zhu et al. 2009). The ewaste recycling processes release significant amounts of BDE209 that are not often detected in the U.S. population Yuan et al. 2008). Although BDE209 has a shorter halflife than less brominated congeners in the environment, it may be degraded to the latter compounds and its toxicity remains to be determined (Birnbaum and Staskal 2004).
Other toxicants: polychlorinated biphenyls, dioxins/furans, polycyclic aromatic hydrocarbons. Polychlorinated biphenyls (PCBs) were present in old transformers and capacitors before their ban in the 1970s, so ewaste recy cling sites that deal with these devices may have high PCBs levels. Contemporary comput ers and cell phones do not contain PCBs. In Taizhou, China, where two sites are involved in ewaste recycling, Luqiao has higher serum ΣPCBs levels in adults (median = 118 ng/g lipid) than Wenling (median = 75 ng/g lipid), presumably because of a focus on PCB containing devices and longer recycling history (Zhao et al. 2010). In another report, children in Luqiao have mean ΣPCBs of 222 ng/g lipid (boys) and 153 ng/g lipid (girls) (Ling et al. 2008). In contrast, adults in Guiyu, China, did not have higher ΣPCBs levels than a non recycling control site (median 52 vs. 63 ng/g lipid, respectively) ), probably because Guiyu has been processing predomi nantly obsolete computers and cell phones.
Informal ewaste recycling also produces secondary emissions that are not chemicals in the ewaste but reaction products from incin eration or smelting processes. Polychlorinated dibenzopdioxins and dibenzofurans (PCDD/ PCDFs) and polycyclic aromatic hydrocarbons (PAHs) can result from open burning of the ewaste (wires or plastics) to reduce volume or to recover metals. Even in primitive recycling sites, open burning of ewaste is usually pro hibited. However, higher PCDD/PCDFs lev els have been reported in breast milk, placenta, and hair samples from ewaste processing sites in Taizhou, China (Chan et al. 2007;Wen et al. 2008). The reported PCDD/PCDFs World Health Organization (WHO) toxic ity equivalent (TEQ) level in breast milk was 21 pg/g lipid in Taizhou (Chan et al. 2007), twice as high as the levels in the United States and many European countries in a WHO coordinated exposure study (van Leeuwen and Malisch 2002). No human studies of PAHs can be identified from ewaste recycling sites, but environmental samples (air, soil, and sedi ment) strongly suggest such contamination exists. The sum of 16 PAHs concentrations in PM 2.5 (particulate matter with aerodynamic diameter ≤ 2.5 µm) air samples was 102 ng/m 3 in a location close to an open burning site in Guiyu, China, much higher than average lev els in Hong Kong (3-4 ng/m 3 ) or Guangzhou (22-58 ng/m 3 ) (Deng et al. 2006).
PCBs are known developmental neuro toxicants, and these compounds may affect a variety of neuropsychological functions in children, including general cognition, visualspatial function, memory, attention, execu tive functions, and motor function (Boucher et al. 2009;Schantz et al. 2003). Most birth cohort studies of prenatal PCB exposure sug gested a harmful role that was not accounted for by other environmental exposures, socio demographic factors, child rearing, and paren tal IQ. The PCB levels in an ewaste recycling site (Taizhou) were in the lowtomoderate range of several international birth cohort studies of PCBs (using CB153 as a criterion, median 30-450 ng/g lipid) (Longnecker et al. 2003). PCDD/PCDFs are often heatdegraded contaminants of PCBs; PCDFs in particular have been indicated to contribute to the two poisoning episodes in Japan and Taiwan (AAP 2003). The analytical testing of PCDD/PCDFs is more difficult, and thus epidemiologic stud ies are rare. However, in the Dutch PCB/ dioxin study, lactational exposure to dioxin (median PCDD/Fs, WHO 1998 TEQ = 33 pg/g lipid in breast milk) was not associ ated with child cognitive abilities at 42 months of age (Patandin et al. 1999;Van den Berg et al. 2006 (Edwards et al. 2010;Perera et al. 2009a;Tang et al. 2008). In the New York City and Polish studies, prenatal PAH exposure above the median (2.26 ng/m 3 in New York City and 17.96 ng/m 3 in Poland) was associated with an IQ deficit of about 3-5 points at 5 years of age (Edwards et al. 2010;Perera et al. 2009a).

Unique Characteristics of E-Waste Toxicant Exposure
First, ewaste toxicants are released in uncon trolled recycling processes as a mixture. It is not uncommon that heavy metals and POPs coexist in the environment in recycling work shops and nearby neighborhoods. Second, the ewaste toxicant exposure is not homo geneous. The variability comes from several sources: the type of ewaste, length of recy cling history, quantity of recycling, speciali zation in recycling processes, locations of workshops, parental involvement in recycling, and the daily activities of the child. Third, the exposure to ewaste toxicants lasts a long time. Many of the recycling sites have oper ated for more than a decade, and cumulative exposure in the local environment is typi cally high. Pregnant women who grew up in the recycling sites would have an even longer exposure history and higher body burden in physiologic deposits (e.g., bones and adipose tissues) than in women who moved in at the time of marriage. Transplacental and lacta tional exposure is expected for most metals and lipophilic organic pollutants in ewaste. Infants and children are exposed from con taminated indoor and outdoor air, dust, and soil. If the food and drinking water also come from contaminated community, the exposure will aggregate to a higher level.

Potential Mechanisms of E-Waste Toxicants and Neurodevelopment
Toxicologic mechanisms of certain individual developmental neurotoxicants, especially Pb, have been investigated extensively, but data are insufficient to address exposure mixtures such as those in ewaste. Apparently several toxicologic mechanisms may be involved in this mixture of known and suspected neuro toxicants, but more research is needed to investigate the combinations of different metals and POPs (Figure 2). These toxico logic mecha nisms are very complicated and may overlap, and other mechanisms related to molecular biology and signal transduction may be involved as well.
Oxidative stress. Heavy metals can induce oxidative stress by increasing the production of reactive oxygen species (ROS) and depletion of antioxidant reserves (Wright and Baccarelli 2007). Neurons have limited capacity to detoxify ROS and are particularly vulnerable to oxidative stress. Pb exposure increases the formation of superoxide anion ( • O 2 -) and hydrogen peroxide (H 2 O 2 ) in the central ner vous system (CNS), which may interact with proteins, lipids, and DNA to induce apop tosis (Sanders et al. 2009). MeHg affects the mitochondria electron transport system and causes overproduction of ROS (Johansson et al. 2007). Cd induces oxidative stress in cultured cells and animals and reduces anti oxidant levels in humans (Joseph 2009;Lee et al. 2006). Exposure to PBDEs increase the generation of ROS, and different PBDEs con geners (e.g., BDE47 and BDE99) may have synergistic interactions in certain concentra tions (Tagliaferri et al. 2010).

N e u r o t r a n s m i s s i o n a n d c a l c i u m homeostasis.
Many heavy metals can affect neurotransmission and disrupt the calcium signaling pathway and thus interfere with synaptic functions. Pb ions (Pb2 + ) selectively bind Nmethyldaspartate (NMDA) recep tor, one subtype of glutamatergic receptors (Toscano and Guilarte 2005). Glutamate is the major excitatory neurotransmitter in the brain tissues and is associated with learning and memory by the establishment of long term potentiation (LTP). Interaction of Pb with the NMDA receptor increases Ca2 + influx, initiating cellular processes that lead to cell dysfunction (Sanders et al. 2009). MeHg exposure can increase Ca2 + levels in different cell types, and it may cause disruptions in cell cycles and migration (Johansson et al. 2007). Cd exposure may modify calcium channels and decrease the release of neurotransmit ters glutamate and aspartate into the synaptic clefts (Minami et al. 2001). A recent animal study suggests that BDE209 exposure reduces LTP and affects synaptic plasticity (Xing et al. 2009). The dopaminergic system is another critical CNS neurotransmission pathway that affects cognition, motivation and reward, attention, and learning. Extensive evidence on the role of environmental toxicants, such as Pb, on synaptic dopamine release, its recep tors and transporters, and metabolism has emerged (Jones and Miller 2008).
Neuroendocrine disruption. Previous research on heavy metals and neurotoxic ity has suggested a similarity to the effects of subtle hypothyroidism, but the evidence is limited (Soldin et al. 2008;Wong et al. 1991). Thyroidstimulating hormone (TSH), T 4 , and triiodothyronine (T 3 ) could have unique effects on the initiation and modula tion of gene expressions for brain develop ment (Porterfield 2000). Animal studies have indicated potential disruption of transthyretin levels in the cerebrospinal fluid and brain deiodinase by Pb, Hg, or Cd (Mori et al. 2006;Soldin and Aschner 2007;Zheng et al. 2001). Pb exposure in occupational workers reduced total T 4 (TT 4 ), free T 4 (FT 4 ), or total T 3 (TT 3 ) (Lopez et al. 2000). Recent studies suggest a reduced level of FT 4 associated with Pb exposure in pregnant women (Lamb et al. 2008) and in adolescents (Dundar et al. 2006), but the results are inconsistent (Maervoet et al. 2007;Schell et al. 2008). In one Canadian study, inorganic Hg was associated with a reduction of FT 4 (Takser et al. 2005), but two other studies found non significant associations in pregnant women and children (Osius et al. 1999;Schell et al. 2008). Cd exposure was found to affect TSH and FT 4 levels in two recent studies (Iijima et al. 2007;Osius et al. 1999), but not in another (Maervoet et al. 2007). The animal studies of PCBs or PBDEs and thyroid hor mone disruption have shown strong correla tions, mostly reducing circulating T 4 or T 3 levels, but human studies are still needed to confirm the effects (Herbstman et al. 2008). A recent epidemiologic study of PBDEs suggests a slight decrease of TSH in exposed pregnant women (Chevrier et al. 2010). One study in ewaste recycling workers revealed higher TSH levels than in controls, and the role of PBDEs are suspected because of their struc tural similarity to T 4 . A recent larger study in ewaste recycling work ers, however, found lower TSH levels than in controls (Wang et al. 2010). Another study suggested a lower TT 4 level in maternal serum in relation to exposure to PCDD/PCDFs and PCBs . Thyroid hormone alteration warrants further study in the expo sure to ewaste toxicants.
Epigenetic modifications. Epigenetic modi fications are mitotically heritable changes of gene function in the absence of alterations in nucleotide sequence. These epigenetic changes include DNA methylation, mostly in the 5´cytosine in the CpG dinucleo tides of the gene promoter region, histone modifications, and microRNAs that affect post transcriptional regulation (Baccarelli and Bollati 2009). Because nucleotide sequence is generally static in somatic cells and epigenetic mark ers are modifiable during the life course, the   Hg, Cd, Cr, PAHs, and PBDEs (Benbrahim Tallaa et al. 2007;Chen et al. 2010;Jiang et al. 2008;Kondo et al. 2006;Onishchenko et al. 2008;Perera et al. 2009b;Pilsner et al. 2009Pilsner et al. , 2010Sun et al. 2009;Takiguchi et al. 2003) (summarized in Table 2). Epigenetic changes may affect gene expression in specific tissues (e.g., brain regions) and subsequently modify neuro development in a critical win dow of development, but the role of neuro toxicants needs to be determined.

Data Gaps in E-Waste Toxicants and Developmental Neurotoxicity
Lack of comprehensive exposure assessment. Comprehensive exposure assessment is urgently needed to characterize the pro files of chemicals and their concentrations, especially in countries where informal ewaste recycling exists on a large scale but exposure assessment is scarce, for example, in India (Ha et al. 2009). Exposure assessment should include both environmental and biological sampling in the recycling sites and control sites to determine the extent of exposure. Exposure of children needs to be examined from in utero to adolescence -in pregnant women (blood, urine, hair), neonates (meco nium, cord blood, breast milk), and children (blood, urine, hair). Toxicant profiles includ ing metals and POPs should be determined in the same study subjects to reflect a realworld exposure scenario of ewaste recycling.

Lack of evaluation of adverse developmental effects.
The demonstration of adverse health effects has historically preceded effec tive pollution control measures. Even though the precautionary principle has gained increas ing attention in developed countries, in devel oping countries observed detrimental health effects are more likely to be a turning point in public opinion and policy making. Research is clearly needed to investigate the health effects of ewaste toxicants resulting from informal recycling activities. These health effects may include fetal development (birth weight, birth length, head circumference, gestational age, thyroid function) and child growth and neuro development (cognition, memory, learning, motor function, executive functions, behavior).
Lack of toxicologic mechanistic research. Ewaste toxicant mixtures have not been exam ined for their potential mechanisms of human developmental toxicity. Even in in vitro or in vivo studies, investigation of mixture toxic ity is rare. In the case of primitive ewaste recy cling, there is a need-and indeed a unique opportunity-to integrate human exposure assessment, adverse health effects, and toxi cologic mechanisms, because such exposure is unprecedented and complex. Mechanistic research that involves new advancements in genomics, epigenetics, and proteomics may provide novel understanding of these known and suspected neurotoxicants. Potential effect modification and synergistic interactions of these toxicants can also be determined in this complex exposure. Mechanistic research can also elucidate the pathway from exposure to internal dose and to biological markers of early adverse effects. Biomarkers including biochemical and epigenetic changes can be reliably assessed in various biospecimens such as blood, urine, buccal swab, and saliva. Integrating mechanistic research into human studies will supplement the findings of ani mal studies with direct evidence of modifiable molecular changes in exposed populations.
Lack of investigation of preventive measures. Although informal ewaste recycling has occurred in developing countries for more than a decade, and high toxicant exposures in vulnerable population have been reported, few attempts have been made to intervene and reduce exposures in the local communities. Research can further determine the major con tributing factors to high toxicant exposures that can be prevented or mitigated. Such fac tors could include locations of recycling work shops relative to residential communities, using houses as recycling workshops or storage, specific recycling processes and technical pro cedures, lack of personal and environmental protection during recycling, lack of additional protection for pregnant women and young children, and nutritional and behavioral factors (iron and zinc deficiency, insufficient vitamin intake, environmental tobacco smoke). These risk factors can be reduced at either a personal or community level and could reduce the expo sures and adverse health effects even if the recy cling activities do not cease immediately.

Perspectives
Investigations. Ewaste is an emerging issue in environmental health, and its potential signifi cance is now being recognized by both scien tists and policy makers. However, serious data gaps exist in the quantification of exposures and health effects. In communities where informal recycling occurs, biomonitoring of exposures, especially in vulnerable pregnant women and young children, provide critical information for epidemiologic investigations, environmental policy making, and informed plans for interven tion. Studies that use sensitive neuro develop mental end points are particularly important in this complex exposure. Other potential tox icities in humans-for example, cancer, respira tory diseases, reproductive functions, and renal effects-should also be examined.
Prevention. A systematic approach guided by exposure assessment and health effect research is needed to prevent toxicant expo sures in ewaste. Engineers, environmental sci entists, and other professionals can participate in the research to minimize exposure to these toxicants. Restricting the use of toxic chemi cals in manufacturing of electronic devices will surely be the upstream of prevention efforts. Appropriate recycling technologies should be the mainstay of ewaste recycling practices. Informal and primitive recycling practices need to be significantly reduced or eliminated. Exposure of children to excessive  Pilsner et al. 2009 Human cord blood leukocytes Maternal exposure associated with global hypomethylation Hg Pilsner et al. 2010 Polar bear brain Brain Hg associated with brain genomic DNA hypomethylation Onishchenko et al. 2008 Mice hippocampus Hypermethylation in brain-derived neurotropic factor gene Cd Takiguchi et al. 2003 Rat liver cells Initial DNA hypomethylation, subsequent DNA hypermethylation after prolonged exposure Benbrahim-Tallaa et al. 2007 Cd-transformed prostate epithelial cells Genomic hypermethylation, hypermethylation in RASSF1A and p16 genes Jiang et al. 2008 Human embryo lung fibroblast cells DNA hypermethylation Cr Kondo et al. 2006 Human lung cancer Hypermethylation in p16 gene Sun et al. 2009 Human lung A549 cells Increased global histone H3 lysine 9 (H3K9) and H3K4 di-and trimethylation, decreased H3K27 trimethylation and histone H3 arginine 2 (H3R2) dimethylation PAHs Perera et al. 2009b Human cord blood leukocytes Hypermethylation of ACLS3 gene promoter region PBDEs Chen et al. 2010 Neonatal rat hippocampal neurons Global DNA hypomethylation ewaste toxicants should be minimized at both household and community levels. Environmental health policies. Effective environmental regulations in ewaste manage ment are needed to prevent excessive exposure to toxicants. Both developed and developing countries share joint responsibility in regu lating electronic device manufacturing and ewaste transboundary movement. In coun tries where primitive recycling processes exist, human health, especially the health of children, needs to drive the regulation and manage ment of recycling activities.