**1. Introduction**

312 Learning Disabilities

Sternberg, R. J. (2003). Giftedness according to the theory of successful intelligence. In N.

Toe, D., Beattie, R., & Barr, M. (2007). The development of pragmatic skills in children who

Van Gent, T., Goedhart, A. W., Hindley, P. A., & Treffers, P. D. (2007). Prevalence and

Wagner, R. K., & Sternberg, R. J. (1986). Tactic knowledge and intelligence in the everyday

Wheeler-Scruggs, K. (2002). Assessing the employment and independence of people who are deaf and low functioning. American Annals of the Deaf, 147(4), 11-17.

and Bacon, ISBN 0205340636, Boston, MA.

Psychology & Psychiatry, 48(10), 950–958.

Press, ISBN 0521317975, Cambridge, UK.

117.

Colangelo & G. Davis (Ed(s).). Handbook of Gifted Education. (pp. 88-99). Allyn

are severely and profoundly deaf. Deafness & Education International, 9(2), 101-

correlates of psychopathology in a sample of deaf adolescents. Journal of Child

world. In R. J. Sternberg & R. K. Wagner (Ed(s).). Practical Intelligence: Nature and origins of competence in the everyday world. (pp. 51-83). Cambridge University

> 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.

#### **2. 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

Environmental Chemical Substances

Agricultural related chemicals Herbicides and metabolites

Insecticides and metabolites

Organochlorines and

Organophosphorus

Organophosphorus insecticides: specific

Pyrethroid pesticide

metabolites

biphenyl

metabolites

insecticides: dialkyl phosphate

insecticides and metabolites

Persistent organic pollutants

Perfluorinated compounds

Polybrominated diphenyl ethers and polybrominated

metabolites

in Relation to Neurodevelopmental Disorders: A Systematic Literature Review 315

Acetochlor mercapturate, Alachlor mercapturate, Atrazine mercapturate, 2,4-Dichlorophenoxyacetic acid, Metolachlor mercapturate, 2,4,5-Trichlorophenoxyacetic

Carbamates, Carbofuranphenol, 2-Isopropoxyphenol

Aldrin, o,p' -Dichlorodiphenyltrichloroethane, p,p' - Dichlorodiphenyltrichloroethane (DDT), p,p' - Dichlorodiphenyldichloroethene (DDE), Dieldrin,

Hexachlorocyclohexane (Lindane), Heptachlor epoxide,

Diethylphosphate (DEP), Dimethylphosphate (DMP), Diethylthiophosphate (DETP), Dimethylthiophosphate

3-Chloro-7-hydroxy-4-methyl-2H-chromen-2-one/ol, 2-

cis -3-(2,2-Dibromovinyl)-2,2-dimethylcyclopropane carboxylic acid, cis -3-(2,2-Dichlorovinyl)-2,2 dimethylcyclopropane carboxylic acid, trans -3-(2,2- Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic

Perfluorobutane sulfonic acid (PFBuS), PFDeA, PFDoA, PFHpA, PFHxS, PFNA, PFOA, PFOS, PFOSA, Et-PFOSA-AcOH, Me-PFOSA-AcOH, PFUA

2,2',4-Tribromodiphenyl ether (BDE 17), BDE 28, BDE 47, 2BDE 66, BDE 85, BDE 99, BDE 100, BDE 153, BDE 154, BDE 183, 2,2',4,4',5,5'-Hexabromobiphenyl (BB 153)

acid, 4-Fluoro-3-phenoxybenzoic acid, 3-

Mirex, trans -Nonachlor, Oxychlordane, 2,4,5- Trichlorophenol, 2,4,6-Trichlorophenol

(DMTP), Diethyldithiophosphate (DEDTP), Dimethyldithiophosphate (DMDTP)

(Diethylamino)-6-methylpyrimidin-4-ol/one, 2- Isopropyl-4-methyl-6-hydroxypyrimidine, Malathion dicarboxylic acid, para -Nitrophenol, 3,5,6-Trichloro-2-

acid, N,N-Diethyl-meta -toluamide (DEET)

Endrin, Hexachlorobenzene, beta - Hexachlorocyclohexane, gamma-

**Categories Chemical substances** 

pyridinol

Phenoxybenzoic acid

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).

Fig. 1. Relationship between ECSs and neurodevelopmental disorders in children. ADHD: attention deficit hyperactivity disorder, LD: learning disability, ASDs: autism spectrum disorders, MR: mental retardation.


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

Lead, Methylmercury, Bisphenol A

study (Table 2) and 168 literatures for animal experiments were listed (Table 3).

**Children's brain**

**LD**

Fig. 1. Relationship between ECSs and neurodevelopmental disorders in children. ADHD: attention deficit hyperactivity disorder, LD: learning disability, ASDs: autism spectrum

> Antimony, Arsenic, Dimethylarsinic Acid, Monomethylarsonic Acid, Trimethylarsine oxide, Barium, Beryllium, Cadmium, Cobalt, Lead, Mercury, Molybdenum, Platinum, Thallium, Tungsten, Uranium

**MR**

Methylmercury?, Unknown

**ASDs** Pesticides

PM10, PM2.5, Carbon monoxide (CO) Sulfur dioxide (SO2), Nitrogen oxides (NOx), Ozone (O3) , Asbestos

Cotinine, NNAL(4-methylnitrosamino)-1-(3-pyridyl)-1-

**Categories Chemical substances** 

butanol)

disorders, MR: mental retardation.

Particulate matters and smoke

Particulate matters

Metals

**ADHD**

Lead, PCBs

Smoking


Environmental Chemical Substances

Hormones and environmental

hormones (endocrine disrupting chemicals) Environmental phenols

Phthalate metabolites

Acrylamide Adducts

Chloromethane related by-

by-products

Products

Phytoestrogens and Metabolites

Other combustion products and

**2.1 Association between ECSs exposure with LD** 

neurodevelopmental disorders in children.

in Relation to Neurodevelopmental Disorders: A Systematic Literature Review 317

Bisphenol A (2,2-bis [4-Hydroxyphenyl] propane), Benzophenone-3 (2-Hydroxy-4-methoxybenzophenone, 4-tert -Octylphenol (4-[1,1,3,3-Tetramethylbutyl] phenol) , Triclosan (2,4,4'-Trichloro-2'-hydroxyphenyl ether)

Mono-benzyl phthalate (MBzP), MiBP, MnBP, MCHP, MEP, MEHP, MEHHP, MEOHP, MECPP, MiNP, MMP,

Daidzein, O-Desmethylangolensin, Enterodiol,

Bromodichloromethane, dibromochloromethane (chlorodibromomethane), Tribromomethane (bromoform), Trichloromethane (chloroform)

Enterolactone, Equol, Genistein

Acrylamide, glycidamide

Table 1. List of ECSs detected in human blood and urine that has been related 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 exposure may be an important role for the preventions of ADHD as well as other

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

**Categories Chemical substances** 

MCPP, MOP


203, PCB 199, PCB 206, PCB 209

PCB 81, PCB 126, PCB 169

1PeCDF, PeCDF, TCDF

Hydroxypyrene

Xylene, m- and p –Xylene

1,2,3,4,7,8,9-

PCB 28, PCB 44, PCB 49, PCB 52, PCB 66, PCB 74), 2,2',3,4,5'- PCB 87, PCB 99, PCB 101, PCB 110, PCB 128, PCB 138 , PCB158, PCB 146, PCB 149, PCB 151, PCB 153, PCB 170, PCB 172, PCB 177, PCB 178, 2,2',3,4,4',5,5'- PCB, 180 PCB 183, PCB 187, PCB 194, PCB 195, PCB 196, PCB

PCB 105, PCB 118, PCB 156, PCB 157, PCB 167, PCB 189, 1,2,3,4,6,7,8-Heptachlorodibenzofuran (HpCDF),

HpCDF, HxCDF, HxCDF, HxCDF, HxCDF, OCDF,

2,3,7,8-Tetrachlorodibenzo-*p*-dioxin (TCDD), HpCDD,

Hydroxyfluorene, 1-Hydroxynaphthalene (1-Naphthol),

Benzene, Chlorobenzene, 1,2-Dibromo-3-chloropropane,

Dichloroethene, Dichloromethane, 1,2-Dichloropropane, 2,5-Dimethylfuran, Ethylbenzene, Hexachloroethane, Methyl tert -butyl ether (MTBE), Nitrobenzene, Styrene, 1,1,2,2-Tetrachloroethane, Perchloroethylene, Carbon tetrachloride, Toluene, Methyl chloroform, 1,1,2- Trichloroethane, Trichloroethene Trichloroethylene, o -

Hydroxyphenanthrene, 2-Hydroxyphenanthrene, 3- Hydroxyphenanthrene, 4-Hydroxyphenanthrene, 1-

HxCDD, HxCDD, HxCDD, OCDD, PeCDD,

2-Hydroxyfluorene, 3-Hydroxyfluorene, 9-

Dibromomethane, 1,2-Dichlorobenzene, m-Dichlorobenzene, Paradichlorobenzene, 1,1- Dichloroethane, Ethylene dichloride, Vinylidene chloride, cis -1,2-Dichloroethene, trans -1,2-

2-Hydroxynaphthalene (2-Naphthol), 1-

**Categories Chemical substances** 

Polychlorinated biphenyls,

Dioxin-like polychlorinated

Coplanar polychlorinated

Mono-ortho-substituted polychlorinated biphenyls

Polychlorinated dibenzofurans

Polychlorinated dibenzo-*p*-

Volatile organic compounds

Polycyclic aromatic hydrocarbon metabolites

non-dioxin-Like

Biphenyls

dioxins

(VOCs)

biphenyls


Table 1. List of ECSs detected in human blood and urine that has been related with LD.
