Autism

20 Autism: Effect of Maternal Exposure to Neurotoxic Chemicals

Chapter Outline 20.1 Autism  287 20.2 Chemical Mixtures  289 20.3 Summary  293 References  294

20.1  Autism Autism spectrum disorder (ASD) is a neurodevelopmental syndrome characterized by communication and social interaction impairments, abnormal movements, repetitive behaviors, and sensory dysfunction [1–3]. It usually manifests itself from 18 months to 3 years, and it is more prevalent in boys than girls and involves noticeable brain differences in those who have it [3]. All autism disorders—autism, Asperger syndrome, other autism-like conditions/atypical autism—may approach 1% of school populations in some areas [4, 5]. In 2007 it was estimated that there is a range in prevalence of 1 in 500 to 1 in 166 children born in the United States [6]. In 2010 it was estimated that 1 in 110 children and 1 in 70 boys born will be afflicted with ASD [7]. Though some of the increases being reported in some areas may be attributed to better diagnoses and record keeping, it is estimated that autism prevalence in the United States is increasing by 17% annually [6]. Autism is seemingly found in every part of the world though its prevalence varies. The highest autism rates are found in the industrialized, developed countries of the world. Though found in the indigenous populations of Africa, the rates there are low [8]. Autism is also virtually unknown in the Amish and Mennonite communities of Pennsylvania and Ohio (D.H. Morton, Clinic for Special Children, Strasburg, PA, July 2004, personal communication) [9]. Several researchers have noted a tendency for parents of autistic children to be highly educated and of higher socioeconomic groups [8, 10]. Autism prevalence data from around the world and, indeed, even within individual countries and states, are sporadic, but they indicate rising rates almost everywhere. For example, autism rates in Iceland increased from 3.8 per 10,000 in the period of 1973–1983 to 8.6 per 10,000 in the period of 1984–1993 [11]. Thirty-one cases of Human Toxicology of Chemical Mixtures. DOI: 10.1016/B978-1-4377-3463-8.00020-5 © 2011 Elsevier Inc. All rights reserved.

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autism per 10,000 births were reported in Sweden in the 1990s [12]; an autism rate of 11.3 per 10,000 births was reported for people native to southern Japan [13]; and rates of 30 per 10,000 in U.S. metropolitan areas were reported in 2003 [14]. It is generally agreed that autism has been increasing worldwide at least since 1979 at a rate of 3.8% per year [15, 16]. As of 2002, the conservative estimate of worldwide prevalence was 10 per 10,000 births [17]. It has since dramatically increased [18]. The available data, however, point in the direction that autism prevalence is lower in rural than in urban areas within the same locale. Autism is prevalent at the rate of 3.06 per 10,000 in the urban areas of Kukishama-Ken in northern Japan and at a rate of 1.18 per 10,000 in rural areas of this region [17]. In this study, it was noted that autism rates were lower when parents worked in agriculture, forestry, fishing, or mining, all presumably rural areas. Among the indigenous peoples of Africa, autism rates are lower than in other parts of the world [8]. Autism is generally believed to have a strong genetic component. Its associated neurological effects are believed to occur in early embryonic development, at 20–24 days of gestation [19]. The initiating injury for autism occurs around the time of neural tube closing [20]. Parents with autism or Asperger syndrome pass these along to offspring [21], and men with Asperger syndrome produce children that are more likely to develop autism [22]. Autism is related to above average head size, something that seems to reflect a large brain. This could be due to a deficit in neural cell pruning brought on by exposure to environmental chemicals [23]. Autism, however, is not believed to be attributable solely to inherited traits [24, 25]. It has been suggested that though a genetic factor is essential, a second deleterious environmental exposure produces a genetic–environmental interaction that ultimately produces autism [3, 16, 22, 26, 27]. Several researchers have suggested that autism may be subject to environmental influences that can include viruses, hormones, intrauterine stresses, and toxicants [27]. Included among these are maternal use of cocaine [28, 29], exposure to rubella virus, valproic acid, or thalidomide during pregnancy [19]. Maternal neurotoxic chemical exposures are also suspected of being associated with increased rates of autism [23]. Here, the case is made for maternal environmental exposure to neurotoxic chemicals as a contributing factor. It has been well established that neurotoxins cause brain damage in the developing fetus and that in the developing fetus the CNS is the most vulnerable of all body systems to injury. Ethanol, cocaine, nicotine, thalidomide, isotriternair, mercury, manganese, lead, dioxins, PCBs, toluene, TCE, xylene, arsenic, carbon tetrachloride, benzene, dichloroethylenes, PCE, trihalmethanes, HAAs, chlorophenols, chloral hydrate, HANs, and perchlorates are but a few of the chemicals known to cause fetal brain damage [23, 30–34]. Prenatal exposure to PCBs has been shown to lower IQ in the offspring [33]. Maternal use of the antiepileptic drug, phenytoin, results in a 10-point decrease in IQ in offspring [35]. Neurotoxic agents can act differently in children than in adults because of their effects on developments, which have no parallels in adults [30]. The developing fetus is more sensitive to neurotoxic agents than adults or even young children [23]. Low levels that are not harmful to adults negatively affect the developing brain [31].

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Different chemicals can cause different injuries at different parts of the fetus’s develop­ ment; that is, different parts are sensitive at different stages of development. A given neurotoxic agent can cause multiple effects, and neurodevelopmental consequences of exposure may vary, since different areas of the brain develop at different times and since dose and timing lead to different outcomes [30, 34, 36]. The nervous, immune, endocrine, and reproductive systems are extensively interconnected and interference with any one of these can have profound effects on any or all of these systems [37].

20.2  Chemical Mixtures Mixtures of chemicals have been shown to produce neurotoxic effects that are not predicted from the known toxicology of the mixtures’ individual chemicals. Low concentrations of chemical mixtures produce unusual and unexpected CNS effects [38–41]. These effects are confounded by concurrent exposure to other toxic chemicals [42]. It is estimated that 28% of all chemicals used in commerce could be neurotoxic [43]. Common household products including air fresheners, fragrance products, marking pens, and mattress covers contain known neurotoxins [44–47]. The neurotoxic effects of marking pens are attributed to chemical mixtures [47]. Aspartame, saccharin, artificial food colors, benzyl alcohol, and other excipients used in pharmaceutical preparations and foods are neurotoxins [48, 49]. Superfund sites are sites that emit numerous neurotoxins into the air and water environments. Love Canal studies have shown nervous system effects that can be attributed to living near a toxic waste site [37]. Elevated neural tube defects in offspring were identified with mothers residing proximate to hazardous waste sites [50, 51]. It has also been shown that people residing close to industrial facilities that emit solvents or metals have offspring with increased CNS defects [52]. The following studies relate autism to environmental factors: 1. In a study in southern Japan, the prevalence rate for natives to the area was 11.3 per 10,000 births. The rate for migrants to the same area was 17.6 per 10,000 births. The native rates fluctuated from year to year in a 4-year cycle, whereas the migrant rates did not. In this study, children born in the second quarter of the year had a higher rate of autism than those born in other times of the year. It was also found that the prevalence of autism was closely related to the number of hospital admissions for pneumonia and bronchitis in the children affected [13]. The rate fluctuations reported in this study cannot be attributed to genetic factors. 2. The literature reports that 36–91% of the time, both monozygotic (MZ) twins are autistic [3, 53–55]. If genetics were the only factor, one would expect dual autism in all MZ twins. 3. The prevalence of autism in an area of northern Japan was studied. The overall prevalence was 2.33 per 10,000 births. The case in the cities, however, was 3.06 per 10,000, and characteristically in rural areas was only 1.18 per 10,000. Autism prevalence was found to be relatively low when parents had rural jobs (forestry, fishing, or mining) and relatively high when fathers had jobs for which higher education is generally required (perhaps relating to urban residence). This study showed that autism rates varied from year to year [17]. Both these factors, the greater autism prevalence in urban than in rural children and the year to year fluctuations in rates, cannot be attributed to genetic factors.

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4. Lotter [8] reported that though autism is found in the indigenous people of Africa, the prevalence seems to be less than in more-developed parts of the world. He also reported that the prevalence of autism in Africa was less in the rural areas than in the urban areas of the continent. Here again, the greater preponderance of autism in urban than in rural areas cannot be attributed to genetics. 5. Autism is virtually unknown in the Amish and Mennonite communities of Lancaster County, Pennsylvania [9]. In these communities, no incidences of autism have been reported in more than 16,000 births from 1988 to 2004. The Amish and Mennonite autism data are the result of 16 years of record keeping among the Amish in Lancaster County, Pennsylvania by Dr. D. Holmes Morton of the Clinic for Special Children in Strasburg, Pennsylvania. This clinic sees every child in the Amish and Mennonite communities in Lancaster County, Pennsylvania with neurological disorders. The Amish and Mennonites live in rural communities. They do not use chemicals or electricity in their daily lives, use only organic farming techniques, and abstain from tobacco and recreational drugs. The absence of autism in these communities strongly suggests a relationship between autism and environmental factors. The Amish and Mennonite communities are insular. Accordingly, it is possible that the lack of autism in these groups could be strictly genetic. This is considered unlikely, however, since they are of German extraction genetically and prevalence of autism in Germans is similar to that in other Western populations. 6. It has been reported that maternal use of cocaine has resulted in an 11.4% rate of autism for offspring [28]. This extremely high rate of autism far exceeds any rate reported in all other studies reported, and strongly suggests an environmental factor. 7. Stromland et al. [19] have reported that children exposed to thalidomide between 20 and 24 days of gestation show a very high rate of autism. Of 86 children so exposed, four subsequently developed autism, a rate that cannot be accounted for by genetics alone. 8. The state of California systematically monitors, collects, and reports autism data statewide on a consistent basis, with the number of cases diagnosed in each county reported on a quarterly basis [56]. The data show lowest autism rates for rural counties, higher values for urban and highly populated suburban counties, and much higher values for Los Angeles County. In 1999 and again in 2003, California issued reports on the prevalence of autism in the state [57, 58]. These reports show autism increasing in the state at the rate of about 3% per year, with the increases greatest in Los Angeles County, lower in the other urban and highly populated suburban counties, and least in the rural counties of the state. Table 20.1 summarizes the California data for the period 2003–2004. This table includes the numbers of autism cases by county and statewide for each of the 2 years, the percent increase of autism by county and statewide, population data for the 2 years, and autism cases per million population in 2004.   The increases in autism prevalence in California have, for the past 20 years, been correspondingly greater in the more highly urbanized areas than in rural areas. The alarmingly high autism prevalence in Los Angeles County is consistent with this observation. These large increases cannot be attributed to improvements in detection, as has been proposed [51], nor can this be attributed to ethnicity, racial identity, or immigration status as has been previously suggested in a much smaller studies [12, 21]. Higher maternal age as has previously been suggested [12], however, can also be ruled out due to the very large annual increase in California autism without a concurrent increase in maternal age. Genetic, mutational changes, or other factors similarly cannot account for the increase in California. During the 1-year period, April 2003–April 2004, the population of California grew by only 1.5% [59], yet autism prevalence increased by 13%. As can be seen from the data in Table 20.1, for the time period, 2003–2004, the population increases in every county were far below the increases in autism cases. Various reasons have been proposed to account for

Autism Cases 2003

  719     0     3   111    17     3   517    11    35   212    12    80     4   365    33    17     6 9375    21    84     8    37    81     1     6    90    54    16 2067

County

Alameda Alpine Amador Butte Calaveras Colusa Contra Costa Del Norte El Dorado Fresno Glenn Humboldt Inyo Kern Kings Lake Lassen Los Angeles Madera Marin Mariposa Mendocino Merced Modoc Mono Monterey Napa Nevada Orange

   816      1      7    128     24      3    582     11     37    281     12     88      5    423     44     18     11 10,663     28     87     11     41     95      1      5    103     65     20   2216 14 17 25  7

a

a

11 17

a

14 33  4

a

16 33  6

a

10

a

 7 33

a

13

a

a

15

a

a

14

Autism Cases Autism % 2004 Increase 2003–2004 1,498,700 1280 36,850 212,700 43,350 20,100 1,003,900 28,250 168,100 862,600 27,750 130,000 18,500 724,900 141,400 63,200 34,850 10,103,000 135,300 250,200 17,650 89,200 232,100 9650 13,500 421,400 131,600 96,100 3,017,300

Population 2004—36,000,000 0.7 0.0 0.5 0.9 1.4 1.8 1.1 0.9 1.3 2.0 1.3 0.9 0.3 2.3 2.0 1.4 2.0 1.4 2.9 0.2 0.6 0.9 2.2 1.0 0.7 1.4 1.2 1.1 1.4

Population % Increase 2003–2004

110 533 163 152 586 393 223 332 438 683 271 597 240 289 322 940 213 338 627 464 419 105 373 249 494 208 734

a

483

(Continued)

Autism Cases per 1,000,000—2004

Table 20.1  Autism Prevalence Rates for California, 2003–2004, Population Data and Autism Cases per 1,000,000 Population in 2004 Autism: Effect of Maternal Exposure to Neurotoxic Chemicals 291

98 4 689 584 18 795 1377 191 256 94 223 232 750 102 82 1 10 193 314 243 29 17 2 121 19 623 75 16

21,209

Placer Plumas Riverside Sacramento San Benito San Bernardino San Diego San Francisco San Joaquin San Luis Obispo San Mateo Santa Barbara Santa Clara Santa Cruz Shasta Sierra Siskiyou Solano Sonoma Stanislaus Sutter Tehama Trinity Tulare Tuolumne Ventura Yolo Yuba

Statewide

24,297

   122      5    825    714     24    928   1529    215    352    116    267    258    906    114     88      1     12    222    355    305     30     18      3    148     22    713     82     19 13

22 16 14  9 19

a

20 15 13 26  3  6

a

20 22 33 17 12 13 38 23 20 11 21 12  7

a

24

Autism Cases Autism % 2004 Increase 2003–2004

Numbers too small to be statistically meaningful.

a

Autism Cases 2003

County

36,144,000

292,100 21,100 1,776,700 1,335,400 57,100 1,866,500 3,017,200 792,700 630,600 258,200 712,400 414,800 1,731,400 260,200 175,700 3520 44,850 416,500 472,700 491,900 85,500 58,700 13,450 396,800 56,900 802,400 184,500 64,800

Population 2004—36,000,000

Table 20.1  (Continued)

1.5

3.0 0.5 3.4 1.8 1.4 2.4 1.4 0.4 2.3 1.1 0.5 1.1 0.7 0.5 1.4 –1.1 0.6 1.0 0.7 1.8 2.0 1.4 1.1 2.1 0.5 1.4 1.9 1.6

Population % Increase 2003–2004

672

418 237 464 535 420 492 462 242 558 449 375 622 523 438 501 284 268 533 722 620 351 307 223 373 387 889 444 293

Autism Cases per 1,000,000—2004

292 Human Toxicology of Chemical Mixtures

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the greatly increased rates in California. These include the suggestion that factors such as hormone levels, diet, and lack of early prenatal care in some groups could be responsible [51]. None of these, however, are supported by the data.   The data in Table 20.1 show the rates of autism are much lower in the rural counties than in the urban ones and that the autism rates in Los Angeles and the surrounding counties (Orange and Ventura) are much higher than those in other urban areas. It should be noted that the autism rates in San Francisco and the surrounding counties (Marin and Santa Cruz) are lower than those in other urban areas, yet even there the rates continue to rise.   It is suggested here that the dramatic increase in autism in California is due to environmental factors. The highly populated areas of California have poor air and water quality, contain numerous neurotoxic chemicals [60–63], and are in close proximity to numerous Superfund sites [60]. This is particularly the case in the Los Angeles area. 9. High rates of autism were suspected in five counties of metropolitan, Atlanta, area [14] and in Brick Township, New Jersey [64]. The data collected show that the values for the Atlanta area and for the Brick Township are similar to those for other large urban areas, including California, other than the Los Angeles area [33]. These high values are attributed to Atlanta’s air pollution [65] and Brick Township’s proximity to several Superfund sites [66].

As noted earlier, there is a tendency for parents of autistic children to be highly educated and of higher socioeconomic groups [8, 10]. This is perhaps so because more highly educated and upper socioeconomic groups tend to live in more environmentally contaminated urban locations than others.

20.3  Summary Cocaine and thalidomide have been identified as causative agents for autism [19, 28]. While other specific environmental chemicals have not yet been definitively identified, one should expect that additional individual chemicals and mixtures of chemicals will be discovered as time goes on. It has been shown that mixtures of lipophilic and hydrophilic chemicals can cause neurotoxic effects at very low concentrations and in ways in which the individual components of the mixtures do not by themselves so act [38–40]. It has also been shown that exposures to specific mixtures of otherwise benign single chemicals have many toxic consequences, including neurotoxic effects [38]. Of the almost infinite number of toxic chemical mixtures possible in the environment, only a very few have been demonstrated to be toxic. If one properly includes food, tobacco, pharmaceuticals, excipients, and recreational drugs in the equation and considers previously published findings [38–40, 67], it is reasonable to assume that at least some of these mixtures do have neurotoxic consequences. It is suggested here that maternal exposures to as yet unspecified chemical mixtures increase the prevalence of autism. Autism certainly has a genetic factor associated with it. Studies, however, showing seasonal and annual variations in its prevalence, increased prevalence in urban versus rural areas, increased prevalence in areas with increased environmental pollution, and increased prevalence in offspring of mothers who have taken certain drugs, lead to the conclusion that there is a connection between the maternal environmental exposure to neurotoxic chemicals and the prevalence of autism.

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A discussion of the environmental causes of autism would not be complete without addressing the question of whether or not thimerosal, a mercury-containing preservative, which was incorporated into childrens’ vaccines for measles, mumps, and rubella (as well as in other vaccines) for many years, is a causative agent. Mercury exposure has been identified with an increased prevalence of autism. In a Texas study, it was found that environmental releases of mercury are related to an increase of more than 60% in the autism rate in the area of release [68]. The effect of mercury from childhood vaccines that contain thimerosal as a possible trigger for autism has been researched and debated extensively. Some believe that thimerosal is not an autism trigger [69] because the autism rates have continued to climb after its use in childrens’ vaccines was discontinued. Others argue that it is plausible that thimerosal is a causative agent for autism [70, 71]. Recently, however, autism has been associated with a urinary porphyrin pattern indicative of mercury toxicity in a large cohort study of French children. In that study, coproporphyrin levels were significantly elevated in children with autism compared to control groups [72]. These results have been duplicated in an American study [73]. The reasons for the elevated mercury levels in the autistic children in these studies are unknown. All children had no known significant mercury exposure other than from thimerosal-containing vaccines that they were given. Why the autistic children and not the non-autistic children (who were also given thimerosal-containing vaccines) retained the mercury in their systems is also unknown. A recent study has found that blood levels of mercury alone are similar in children with ASD and free of ASD, even when dietetic consumption of mercury (through the eating of fish) was taken into consideration [74]. To date, no one has studied the effects of mixtures of thimerosal with other chemicals. As of this time (2011) it is felt that mercury alone is not the cause of the increased incidence of autism, but that environmental factors are. The average prevalence of ASD increased 57% in children aged 8 years from 2002 to 2006. This cannot be accounted for by genetics or better reporting [75]. Recent research has tied autism prevalence to exposures to inflammatory agents (chemical and biological) that have also been tied to asthma rate increases [76]. It has been suggested that acetaminophen, which is suspected as causing an increase in asthma, may also be responsible for increases in autism, particularly since the exponential rise in autism corresponds with the increase of acetaminophen in children [77–81]. This, too, remains an open question at this time, with research ongoing. A study of almost 5000 children in Sweden has shown that indoor air pollutants are known to cause asthma in that group, and may also be causative for ASD. The factors identified included secondhand cigarette smoke, PVC flooring in the home, and low ventilation rates [78]. Though the studies just cited do not “prove” the associations described, they are strongly suggestive and warrant the more intensive investigation that is currently ongoing.

References [1] S. Bernard, A. Enayati, H. Roger, et al., The role of mercury in the pathogenesis of autism, Mol. Psychiatry 7 (2002) S42–S43.

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[2] L.R. Goldman, S. Koduru, Chemicals in the environment and developmental toxicity to children: a public health and policy perspective, Environ. Health Perspect. 108 (Suppl. 3) (2000) 443–448. [3] H. Jick, J.A. Kaye, Epidemiology and possible causes of autism, Pharmacotherapy 23 (12) (2003) 1524–1530. [4] B. Kadesjo, C. Gillberg, B.H. Gillberg, Brief report: autism and Asperger syndrome in seven-year old children: a total population, J. Autism Dev. Disord. 29 (4) (1999) 327–331. [5] L. Wing, D. Potter, The epidemiology of autistic spectrum disorders: is the prevalence rising? Ment. Retard. Dev. Disabil. Res. Rev. 8 (3) (2002) 151–161. [6] Centers for Disease Control and Prevention, New Data on Autism Spectrum Disorders, Atlanta, GA, February 8. Available from: www.cdc.gov, 2007. [7] K.C. Van Meter, L.E. Christiansen, L.D. Delwiche, et al., Geographic distribution of autism in California: a retrospective birth cohort analysis, Autism Res. 2 (2009) 1–11. [8] V. Lotter, Childhood autism in Africa, J. Child Psychol. Psychiatry 19 (1978) 231–244. [9] Clinic for Special Children, Strasburg, PA. Available from: http://.clinicforspecialchildren. com/. [10] V.D. Sanua, Is infantile autism a universal phenomenon? An open question, Int. J. Soc. Psychiatry 30 (3) (1984) 163–177. [11] P. Magnusson, D. Saemendsen, Prevalence of autism in Iceland, J. Autism Dev. Disord. 31 (2) (2001) 153–163. [12] T. Arvidsson, B. Danielson, P. Forsberg, et al., Autism in 3–6-year old children in a suburb of Goteborg, Sweden, Autism 1 (2) (1997) 163–173. [13] Y. Tanoue, S. Oda, F. Asano, K. Kawashima, Epidemiology of infantile autism in southern Ibaraki, Japan: differences in prevalence in birth cohorts, J. Autism Dev. Disord. 18 (2) (1988) 155–166. [14] M. Yeargin-Allsopp, C. Rice, T. Karapurkar, et al., Prevalence of autism in a US metropolitan area, J. Am. Med. Assoc. 289 (1) (2003) 49–55. [15] E. Fombonne, Epidemiological trends in rates of autism, Mol. Psychiatry 7 (2002) S4–S6. [16] E. London, R.A. Etzel, The environment as an etiologic factor in autism: a new direction for research, Environ. Health Perspect. 108 (Suppl. 3) (2000) 401–404. [17] Y. Hoshino, H. Kumashiro, Y. Yashima, The epidemiological study of autism in Fukushima-ken, Folia Psychiatr. Neurol. Jpn. 36 (2) (1982) 115–124. [18] C.S. Price, W.W. Thompson, D. Goodson, et al., Prenatal and infant exposure to thimerosal from vaccines and immunoglobulins and risk for autism, Pediatrics 126 (4) (2010) 856–864. [19] K. Stromland, V. Nordin, M. Miller, et al., Autism in thalidomide embryopathy: a population study, Dev. Med. Child Neurol. 36 (4) (1994) 351–366. [20] P.M. Rodier, J.L. Ingram, B. Tisdale, et al., Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei, J. Comp. Neurol. 370 (2) (1996) 247–261. [21] I.C. Gillberg, C. Gillberg, Autism in immigrants: a population-based study from Swedish rural and urban areas, J. Intellect. Disabil. Res. 40 (Part I) (1996) 24–31. [22] C. Gillberg, H. Schaumann, I.C. Gillberg, Autism in immigrants: children born in Sweden to mothers born in Uganda, J. Intellect. Disabil. Res. 39 (Part 2) (1995) 141–144. [23] P.M. Rodier, Environmental causes of central nervous system maldevelopment, Pediatrics 113 (4) (2004) 1076–1083. [24] S. Steffenberg, C. Gillberg, L. Hellgren, et al., A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden, J. Child Psychol. Psychiatry 30 (3) (1989) 405–416. [25] W.R. Kates, C.P. Burnette, S. Eliez, et al., Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism, Am. J. Psychiatry 161 (3) (2004) 539–546.

296

Human Toxicology of Chemical Mixtures

[26] F. DeStefano, R.T. Chen, Autism and measles–mumps–rubella vaccination. Controversy laid to rest? CNS Drugs 15 (11) (2001) 831–837. [27] C.M. Hultman, P. Sparen, S. Cnattingius, Perinatal factors for infantile autism, Epidemiology 13 (4) (2002) 417–423. [28] E. Davis, I. Fennoy, D. Laraque, et al., Autism and developmental abnormalities in children with perinatal cocaine exposure, J. Natl. Med. Assoc. 84 (4) (1992) 315–319. [29] A.S. Oro, S.D. Dixon, Perinatal cocaine and methamphetamine exposure: maternal and neonatal correlates, J. Pediatr. 111 (1997) 571–578. [30] P. Mendola, S.G. Selevan, S. Gutter, D. Rice, Environmental factors associated with a spectrum of neurodevelopmental deficits, Ment. Retard. Dev. Disabil. Res. Rev. 8 (2002) 188–197. [31] T. Schletter, Toxic threats to neurologic development in children, Environ. Health Perspect. 109 (Suppl. 6) (2001) 813–816. [32] K. Nakai, H. Satoh, Developmental neurotoxicity following prenatal exposure to methylmercury and PCBs in humans from epidemiological studies, Tohoku J. Exp. Med. 196 (2002) 89–98. [33] N. Ribas-Fito, M. Sala, M. Kogevinas, J. Sunyer, Polychlorinated biphenyls (PCBs) and neurological development in children: a systematic review, J. Epidemiol. Commun. Health 55 (2001) 537–546. [34] F.J. Bove, M.C. Fulcomer, J.B. Klotz, et al., Public drinking water contamination and birth outcomes, Am. J. Epidemiol. 141 (9) (1995) 850–862. [35] D. Scolnik, I. Nulman, J. Rovet, et al., Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy, J. Am. Med. Assoc. 271 (10) (1994) 767–770. [36] D. Laslo-Baker, M. Barrera, D. Knittel-Keren, et al., Child neurodevelopmental outcome and maternal occupational exposure to solvents, Arch. Pediatr. Adolesc. Med. 158 (10) (2004) 956–961. [37] D.O. Carpenter, Human health effects of environmental pollutants: new insights, Environ. Monit. Assess. 53 (1998) 245–258. [38] H.I. Zeliger, Toxic effects of chemical mixtures, Arch. Environ. Health 58 (1) (2003) 23–29. [39] M.B. Abou-Donia, A.M. Dechkovskaia, L.B. Goldstein, et al., Co-exposure to pyridostigmine bromide, DEET, and/or premethrin causes sensorimotor deficit and alterations in brain acetylcholinesterase activity, Pharmacol. Biochem. Behav. 77 (2004) 253–262. [40] W.P. Porter, J.W. Jaeger, I.H. Carlson, Endocrine, immune and behavioral effects of aldicarb (carbamate), atrazine (triazine) and nitrate (fertilizer) mixtures at groundwater concentrations, Toxicol. Ind. Health 15 (1–2) (1999) 133–150. [41] D.A. Jett, R.V. Navoa, M.A. Lyons Jr., Additive inhibitory action of chlorpyrifos and polycyclic aromatic hydrocarbons on acetylcholinesterase activity in vitro, Toxicol. Lett. 105 (3) (1999) 223–229. [42] C.G. Graves, G.M. Matanoski, R.G. Tardiff, Weight of evidence for an association between adverse reproductive and developmental effects and exposure to disinfection by-products: a critical review, Regul. Toxicol. Pharm. 34 (2001) 103–124. [43] National Environmental Trust, Washington, DC, Physicians for Social Responsibility, Washington, DC, Learning Disabilities Association of America, Pittsburgh, PA. Polluting our future: Chemical pollution in the U.S. that affects child development and learning. Available from: www.safekidsinfo.org, March 2004. [44] R.C. Anderson, J.H. Anderson, Toxic effects of air freshener emissions, Arch. Environ. Health 52 (6) (1997) 433–441.

Autism: Effect of Maternal Exposure to Neurotoxic Chemicals

297

[45] R.C. Anderson, J.H. Anderson, Acute toxic effects of fragrance products, Arch. Environ. Health 53 (2) (1998) 138–146. [46] R.C. Anderson, J.H. Anderson, Respiratory toxicity in mice exposed to mattress covers, Arch. Environ. Health 54 (3) (1999) 202–209. [47] R.C. Anderson, J.H. Anderson, Acute toxicity of marking pen emissions, J. Toxicol. Environ. Health Part A 66 (2003) 829–845 [48] B.F. Finegold, Dietary management of nystagmus, J. Neural Transm. 45 (2) (1979) 107–116. [49] American Academy of Pediatrics Committee on Drugs, Inactive ingredients in pharmaceutical products: update, Pediatrics 99 (2) (1997) 268–278. [50] L.A. Croen, G.M. Shaw, L. Sanbonmatsu, et al., Maternal residential proximity to hazardous waste sites and risk for selected congenital malformations, Epidemiology 8 (4) (1997) 347–354. [51] L.A. Croen, J.K. Grether, S. Sevin, Descriptive epidemiology of autism in California population: who is at risk? J. Autism Dev. Disord. 32 (3) (2002) 217–224. [52] E.G. Marshall, L.J. Gersburg, D.A. Deres, et al., Maternal residential exposure to hazardous wastes and risk of central nervous system and musculoskeletal birth defects, Arch. Environ. Health 52 (6) (1997) 416–425. [53] D.A. Greenberg, S.E. Hodge, J. Sowinski, D. Nicoll, Excess of twins among affected sibling pairs with autism: implications for the etiology of autism, Am. J. Hum. Genet. 69 (2001) 1062–1067. [54] R. Muhle, S.V. Trentacoste, I. Rapin, The genetics of autism, Pediatrics 113 (5) (2004) 472–486. [55] A. Bailey, A. Le Couteur, E. Gottesman, et al., Autism as a strongly genetic disorder: evidence from a British twin study, Psychol. Med. 25 (1995) 63–77. [56] California Department of Developmental Services, Sacramento, CA. Reports on Autism in California. Available from: http://www.dds.ca.gov/FactsStats/diagnostic_info.cfm, July 2004. [57] California Department of Developmental Services, Changes in the population of persons with autism and pervasive developmental disorders in California’s developmental services system: 1987 through 1998, March 1999. Department of Developmental Services, 1600 9th St., Rm. 240, Sacramento, CA. [58] California Department of Developmental Services, Autistic spectrum disorders, changes in the California caseload, an update: 1999–2002, May 2003. Department of Developmental Services, 1600 9th St., Rm. 240, Sacramento, CA. [59] Department of Finance, State of California, Sacramento CA. Population estimates with annual percentage change 2003 to 2004, May 5, 2004. [60] California Environmental Protection Agency, Air Resources Board, The California Almanac of Emissions and Air Quality, 2005 ed., Air Resources Board, Sacramento, CA, 2005. [61] S.H. Swan, K. Waller, B. Hopkins, et al., A prospective study of spontaneous abortion: relation to amount and source of drinking water consumed in early pregnancy, Epidemiology 9 (2) (1998) 126–133. [62] E.T. Urbansky, Perchlorate as an environmental contaminant, Environ. Sci. Pollut. Res. 9 (3) (2002) 187–192. [63] EPA (United States Environmental Protective Agency), National Priorities List Sites in California. Available from: http://www.epa.gov/superfund/sites/npl/ca.htm, June 7, 2004. [64] Centers for Disease Control and Prevention, Prevalence of autism in Brick Township, New Jersey, 1988: Community Report, Atlanta, GA, April 2000.

298

Human Toxicology of Chemical Mixtures

[65] Georgia Department of Natural Resources, Environmental Protection Division, Air Protection Branch, Ambient Monitoring Program. Available from: www.gadnr.org/ epd/air/amp/. [66] New Jersey Department of Environmental Protection, Site Remediation and Waste Management Program. New Jersey Superfund sites. Available from: www.nj.gov/dep/ srp/community. [67] H.I. Zeliger, Cancer clusters: common threads, Arch. Environ. Health 54 (3) (2004) 172–176. [68] R.F. Palmer, S. Blanchard, Z. Stein, et al., Environmental mercury release, special education rates and autism disorder: an ecological study in Texas, Health Place 12 (2) (2006) 203–209. [69] M. Shevell, E. Fombonne, Autism and MMR vaccination or thimerosal exposure: an urban legend? Can. J. Neurol. Sci. 33 (4) (2006) 339–340. [70] M.F. Blaxill, L. Redwood, S. Bernard, Thimerosal and autism? A plausible hypothesis that should not be dismissed, Med. Hypothesis 62 (5) (2004) 788–794. [71] D.A. Geier, M.R. Geier, A case series of children with apparent mercury toxic encephalopathies manifesting with clinical symptoms of regressive autistic disorders, J. Toxicol. Environ. Health A 70 (10) (2007) 837–851. [72] R. Nataf, C. Skorupka, L. Amet, et al., Porphyrinuria in childhood autistic disorder: implications for environmental toxicity, Toxicol. Appl. Pharmacol. 214 (2) (2006) 99–108. [73] D.A. Geier, M.R. Geier, A prospective assessment of porphyrins in autistic disorders: a potential marker for heavy metal exposure, Neurotox. Res. 10 (1) (2006) 57–64. [74] I. Hertz-Picciotto, P.G. Green, L. Delwiche, Blood mercury concentrations in CHARGE study children with and without autism, Environ. Health Perspect. 118 (1) (2010) 161–166. [75] Centers for Disease Control, Prevalence to autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, United States, 2006, MMWR Surveill. Summ. 58 (10) (2009) 1–20. [76] K.G. Becker, Autism, asthma, inflammation, and the hygiene hypothesis, Med. Hypotheses 69 (4) (2007) 731–740. [77] K.G. Becker, S.T. Schultz, Similarities in features of autism and asthma and possible link to acetaminophen, Med. Hypotheses 74 (1) (2010) 7–11. [78] M. Larsson, B. Weiss, S. Janson, et al., Associations between indoor environmental factors and parental-reported autistic spectrum disorders in children 6–8 years of age, Neurotoxicology 30 (5) (2009) 822–831. [79] S.T. Schultz, Can autism be triggered by acetaminophen activation of the endocannabinoid system, Acta Neurobiol. Exp. 70 (2010) 227–231. [80] P. Good, Did acetaminophen provoke the autism epidemic? Alt. Med. Rev. 14 (2009) 364–372. [81] A.K. Halladay, D. Amaral, M. Aschner, et al., Animal models of autism spectrum disorders: information for neurotoxicologists, Neurotoxicology 30 (2009) 811–821.