Environmental Chemical Substances in Relation to Neurodevelopmental Disorders: A Systematic Literature Review

Since the 1950s-70s, increasing number of regulations have rapidly expanded for the global usage of industrial, agricultural and other environmental chemical substances (ECSs). It is believed that children are at high risk of exposure to ECSs, which are produced in quantities greater than one million tons per year and widely dispersed in air, water, food crops, communities, waste sites and homes (Landrigan et al. 2006). Prevalence rates of many common diseases in children, including certain childhood cancers (Devesa et al. 1995; Robison et al. 1995; Schechter 1999; Supriyadi et al. 2011), birth defects (Ananth et al. 2005; Gilboa et al. 2010) and neurodevelopmental disorders (Malik et al. 2011), have been increased or maintained at high levels in industrialized countries. Although primary etiologic factors contributing to these diseases are unknown yet, accumulating evidences indicate that exposure to ECSs are partially responsible for the developmental disabilities, such as autism spectrum disorders (ASDs), attention deficit hyperactivity disorder (ADHD), and other developmental delays (Boyle et al. 2011; Larson et al. 2001) (Figure 1). In this chapter, we conducted a systematic literature review for neurotoxic agents in environment to elucidate the relationship between exposure to ECSs and neurodevelopment disorders in children.


Introduction
Since the 1950s-70s, increasing number of regulations have rapidly expanded for the global usage of industrial, agricultural and other environmental chemical substances (ECSs).It is believed that children are at high risk of exposure to ECSs, which are produced in quantities greater than one million tons per year and widely dispersed in air, water, food crops, communities, waste sites and homes (Landrigan et al. 2006).Prevalence rates of many common diseases in children, including certain childhood cancers (Devesa et al. 1995;Robison et al. 1995;Schechter 1999;Supriyadi et al. 2011), birth defects (Ananth et al. 2005;Gilboa et al. 2010) and neurodevelopmental disorders (Malik et al. 2011), have been increased or maintained at high levels in industrialized countries.Although primary etiologic factors contributing to these diseases are unknown yet, accumulating evidences indicate that exposure to ECSs are partially responsible for the developmental disabilities, such as autism spectrum disorders (ASDs), attention deficit hyperactivity disorder (ADHD), and other developmental delays (Boyle et al. 2011;Larson et al. 2001) (Figure 1).In this chapter, we conducted a systematic literature review for neurotoxic agents in environment to elucidate the relationship between exposure to ECSs and neurodevelopment disorders in children.

Exposure to ECSs and neurodevelopmental disorders in children
According to the Fourth National Report on Human Exposure to Environmental Chemicals (Fourth Report), 212 ECSs were detected in the urine and blood samples from the civilian, noninstitutionalized U.S. population (CDC 2009).Therefore, we searched literatures for these 212 ECSs with keywords of "learning disabilities", "developmental delay" and "autism" by PubMed (http://www.ncbi.nlm.nih.gov/pubmed), and then a total of 1075 literatures were selected published during 1972 -2011 July.These ECSs were categorized by their chemical features in this review (Table 1).Neurodevelopmental disorders in children are disabilities associated primarily with the functionings of the neurological system and brain, which include ADHD, ASDs, mental retardation (MR) and learning disabilities (LD).It has been known that children with neurodevelopmental disorders experience problems with language and speech, motor skills, behavior, memory, learning, or other neurological functions.Therefore, we further selected important papers by the review of the keywords, such as children, exposure, neurobehavioral, neurotoxicity, neuropsychological, disabilities, cognitive, development, behavior and school-aged for human study and learning memory, exposure, neurobehavioral, neurodegeneration, neurogenesis, neuropathological, neurotoxicity, impairments, deficits, behavior, hippocampus, developmental, cognitive, disorders, receptors and model for animal studies.Here, a total of 142 literatures for human study (Table 2) and 168 literatures for animal experiments were listed (Table 3).

Categories
Chemical substances Hormones and environmental hormones (endocrine disrupting chemicals) Environmental phenols

Phytoestrogens and Metabolites
Bisphenol A (2, propane), 1,3,  Table 1.List of ECSs detected in human blood and urine that has been related with LD.

Association between ECSs exposure with LD
Studies have found that several widespread environmental contaminants can damage the children's developing brains and nervous systems.In our literature review, lead, methylmercury, pesticides, tobacco (cotinine), persistent organic pollutants such as polychlorinated biphenyls (PCBs), and environmental hormones such as bisphenol A and phthalates have been indicated association between neuronal disability and exposure levels in children (Table 3).For instances, prenatal tobacco and childhood lead exposures may be significant risk factors for ADHD, especially when individuals are exposed to both of these toxicants (Froehlich et al. 2009).Although the U.S. has made considerable strides in reducing these toxicant exposure, 15% of women reported smoking during pregnancy in the U.S. population-based study in 2004 (Allen et al. 2008), and an estimated 1.6% of U.S. children showed blood lead levels of concern (≥10 µg/dL) in 1999-2002, with almost 14% having levels of 5 to 9 µg/dL (CDC 2005).These findings suggest that reduction of toxicant e x p o s u r e m a y b e a n i m p o r t a n t r o l e f o r t h e p r e v e n t i o n s o f A D H D a s w e l l a s o t h e r neurodevelopmental disorders in children.
In addition, the accumulating evidences suggest a link between lead exposure and memory impairment.van Wijngaarden et al. (2009) conducted a pilot study of 47 healthy subjects aged 55-67 years to examine associations between bone lead levels and 4 tests sensitive to the natural history of Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD), which included 3 subtests of the Cambridge Neuropsychological Test Automated Battery (delayed match-to-sample, paired associates learning and spatial recognition memory) and the Montreal Cognitive Assessment Test.By measurements of bone lead concentrations, higher tibial and calcaneal bone lead values were significantly (p<0.05)associated with lower performance levels on delayed match-to-sample and paired associates learning in unadjusted analyses with Spearman rank correlation coefficients of about 0.4.Multiple linear regression analyses (i.e., least-squares means of cognitive test scores across tertiles of lead exposure) adjusted for age, education and smoking status continued to show an association of higher calcaneal lead levels with increasing memory impairments on delayed match-to-sample (p=0.07).As might be expected, additional adjustment for history of hypertension reduced the strength of this association (p=0.19).Given the demonstrated impact of lead exposure on hypertension and the vascular aetiology of certain dementias, authors speculated that hypertension could play a mediating role in the association between lead exposure and memory impairment.
Pesticides and their degradation products are ubiquitous in the environment.The most commonly detected indoor pesticides (organophosphates and pyrethroids), which are routinely applied in classrooms and playgrounds, are well-known neurotoxicants that affect the ability to learn and process information (Tulve et al. 2006).In our literature survey, Xu et al. (2011) examined the association between body burden of trichlorophenol (TCP) (ie, 2,4,5-TCP and 2,4,6-TCP) and ADHD by logistic regression analyses using data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES) to evaluate the association between urinary TCPs and parent-reported ADHD among 2546 children aged 6-15 years.Their results showed that children with low levels (<3.58 μg/g) and high levels (≥3.58 μg/g) of urinary 2,4,6-TCP had a higher risk of parent-reported ADHD compared to children with levels below the limit of detection (OR 1.54, 95% CI 0.97 to 2.43 and OR 1.77, 95% CI 1.18 to 2.66, respectively; p for trend=0.006)after adjusting for covariates.No association was found between urinary 2,4,5-TCP and parent-reported ADHD.These results suggested that exposure to TCP may increase the risk of behavioural impairment in children, especially in countries where organochlorine pesticides are still commonly used.It also should be noted that Rauh et al. (2006) reported the impact of prenatal exposure to chlorpyrifos on 3-year neurodevelopment and behavior in city-residential minority 254 children.The report examined cognitive and motor development with the Bayley Scales of Infant Development II and child behavior with the Child Behavior Checklist and chlorpyrifos levels in umbilical cord plasma.Highly exposed children (chlorpyrifos levels of >6.17 pg/g plasma) scored, on average, 6.5 points lower on the Bayley Psychomotor Development Index and 3.3 points lower on the Bayley Mental Development Index at 3 years of age compared with those with lower levels of exposure.Children exposed to higher in compared with lower chlorpyrifos levels were also significantly more likely to experience Psychomotor Development Index and Mental Development Index delays, which are attention problems, ADHD problems, and pervasive developmental disorder problems at 3 years of age.The proportion of delayed children in the high-exposure group, compared with the low-exposure group, was 5 times greater for the Psychomotor Development Index and 2.4 times greater for the Mental Development Index.
It was also reported that children prenatally exposed to PCBs might be related with lowered intelligence and behavioral deficits.Relationships between adverse health effects and PCB exposure during infancy and childhood have been examined.Although some inconsistencies in the literature exist, the overall evidence supports a concern for adverse effects of PCBs on children's neurological development.It should be noted that adverse effects on intelligence and behavior have been found in girls who were highly exposed to mixtures of PCBs, chlorinated dibenzofurans, and other pollutants prior to conception (Chen et al. 1992;Chen et al. 1994).

Possible mechanism of ECSs-induced autism and developmental delay
As above mentioned, several ECSs have been related with developmental delay such as ADHD and LD in human studies.However, little is known about the underlying mechanism by which ECSs could induce developmental delay.Animal experiments and in vitro studies using cells are useful to elucidate these kinds of mechanisms and understand the results of human studies.Animal studies listed in Table 3 indicate that most attentions have been focused on lead, mercury, pesticides and polycyclic aromatic hydrocarbons (PAHs).For example, toxic properties of lead have been attributed to its capability to mimic calcium and alter calcium homeostasis.One of the reasons for the deleterious effects of lead is its ability to strongly bind to sulfhydryl groups of proteins and to mimic or compete with calcium (Flora et al. 2007).It is known that lead, even at picomolar concentration, competes with calcium for binding sites on cerebellar phosphokinase C, thereby affecting neuronal signaling and neurotransmitter release (Bressler and Goldstein 1991), inhibiting calcium entry into cells (Simons 1993).Lead disrupts mitochondrial calcium homeostasis, intercellular oxidants levels, ATP production, and apoptogenic factors.
Rats in the benzo(a)pyrene (B(a)P) -treated groups have significantly impaired Morris water maze performance when compared to controls (Chengzhi et al. 2011).The B(a)P-induced neuronal damage was found in the hippocampus under transmission electron microscopy.
Their results demonstrated that LM deficits associated protein expression signatures could be identified from tissue proteomes, as well as potential biomarkers such as retinoic acid receptor b (RARb), synaptotagmin iosfomrs 1 (Syt1) and brain-derived neurotrophic factor (BDNF).This finding is the first time that multiple novel proteins that are dysregulated by B(a)P, which both enhance our understanding of B(a)P induced locomotor deficits and represent targets of novel therapeutics.Prenatal morphine can alter the synaptic complex of postsynaptic density 95 with N-methyl-D-aspartate receptor subunit in hippocampal CA1 subregion of rat offspring leading to long-term cognitive deficits (Lin et al. 2009).This morphine model might be useful for understanding mechanisms of long-term cognitive deficit induced by other ECSs such as lead and PCBs.
Originally, organophosphate pesticides (OPs) have been thought to exert their effects on brain development secondarily by their ability to inhibit cholinesterase.However, it became now clear that these agents act as developmental neurotoxicants through a number of differential mechanisms.Some of which operate at exposures below the threshold for cholinesterase inhibition may differ in their effects on brain development and their consequent impacts on behavioral performance (Paul et al. 1994;Cohn and MacPhail 1997;Itoh et al. 1997aItoh et al. , 1997b;;Palumbo et al. 2001;Castillo et al. 2002;Levin et al. 2002;Aldridge et al. 2005;Spowart-Manning and van der Staay 2005;Timofeeva, 2008;Verma et al. 2009;Levin et al. 2010).A series of studies with toxico-dynamically equivalent exposures in neonatal rats showed that chlorpyrifos, diazinon and parathion (PRT) elicit behavioral abnormalities in association with adverse effects on acetylcholine (ACh) and serotonin (5HT) circuits, but that the underlying defects and behavioral outcomes differ among the three OPs.In particular, PRT exposure did not elicit the cognitive impairment noted with the other two OPs, as evaluated in the radial-arm maze in adolescence and young adulthood, although, it did share adverse effects on indices of ACh synaptic function.

Conclusion
ECSs are distributed widely and in increasing amounts over the world in the last few decades.ECSs exposure could occur through breastfeeding and hand-to-mouth activities in small children.In this review, epidemiological studies of children between ECSs exposure and neurodevelopmental disorders and experimental animal studies were focused.In our literature review, lead, methylmercury, pesticides, tobacco (cotinine), persistent organic pollutants such as PCBs, and environmental hormones such as bisphenol A and phthalates have been indicated association between neuronal disability and exposure levels in children.
Children's brain and nervous system are vulnerable to adverse impacts from pollutants because they go through a long developmental process beginning shortly after conception and continuing through adolescence.This complex developmental process requires the precise coordination of cell growth and movement, and may be disrupted by even shortterm exposures to environmental contaminants if they occur at critical periods of development.This disruption can lead to neurodevelopmental deficits that may have an effect on the children's achievements and behaviors even though they do not result in a diagnosable disorder.

Acknowledgment
The authors thank Dr. Yoshika Kurokawa and Dr. Masami Ishido for their invaluable suggestions.

Table 3
. Literature lists for effects of environmental chemicals on memory and cognition in experimental animal models.