Environmental Chemical Exposures and Autism Spectrum Disorders: A Review of the Epidemiological Evidence

May combine two claims.

Results of included studies on direct maternal smoking in pregnancy and ASD were scattered above and below the null, with most confidence intervals crossing the null, consistent with no association overall.

“Results of these studies were scattered above and below the null, with most confidence intervals crossing the null, consistent with no association between direct maternal smoking in pregnancy and Autism Spectrum Disorder diagnosis, overall (Fig. 1).”

May combine two claims.

The direction of social class confounding differed by country: in the U.S. and Canada associations were higher after adjustment, whereas in European countries associations were attenuated after adjustment.

“In the U.S. and Canada, associations were higher after adjusting for sociodemographic variables,52,57 whereas in European countries (Sweden, Finland, and Norway), associations were attenuated after adjustment.51,53,58,59”

• cites [52] Kalkbrenner, 2012, Maternal smoking during pregnancy and the prevalence of autism spectrum disorders, using data from the autism and developmental disabilities monitoring network, Environ Health Perspect sourceNot checked yet

  Not checked in the free run.

• cites [57] Burstyn, 2010, Autism spectrum disorders, maternal characteristics and obstetric complications among singletons born in Alberta, Canada, Chronic Dis Can sourceNot checked yet

  Not checked in the free run.

• cites [51] Lee, 2011, Brief report: maternal smoking during pregnancy and autism spectrum disorders, J Autism Dev Disord sourceNot checked yet

  Not checked in the free run.

• cites [53] Indredavik, 2007, Prenatal smoking exposure and psychiatric symptoms in adolescence, Acta Paediatr sourceNot checked yet

  Not checked in the free run.

• cites [58] Larsson, 2009, Associations between indoor environmental factors and parental-reported autistic spectrum disorders in children 6–8 years of age, Neurotoxicology sourceNot checked yet

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• cites [59] Tran, 2013, Smoking during pregnancy and risk of autism spectrum disorder in a Finnish national birth cohort: smoking during pregnancy and risk of autism, Paediatr Perinat Epidemiol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Confounding by family social characteristics was expected, but its degree was not strong and acted in opposite directions across studies, attenuating ORs in some studies and producing elevated ORs in others.

“Although confounding by such family social characteristics was expected, the degree of this confounding was not strong and acted in opposite directions across studies, attenuating ORs in some studies71,72 and producing elevated ORs in other studies.73,74”

• cites [71] Volk, 2011, Residential proximity to freeways and autism in the CHARGE study, Environ Health Perspect sourceNot checked yet

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• cites [72] Volk, 2013, Traffic-related air pollution, particulate matter, and autism, J Am Med Assoc PsychiatryNot checked yet

  Not checked in the free run.

• cites [73] Becerra, 2012, Ambient air pollution and autism in Los Angeles County, California, Environ Health Perspect sourceNot checked yet

  Not checked in the free run.

• cites [74] Kalkbrenner, 2013, Exposure to ambient coarse particulate matter by gestational period and autism spectrum disorders in North Carolina and California, Am J EpidemiolNot checked yet

  Not checked in the free run.

May combine two claims.

Results showed elevated associations between autism and mixed air pollutant exposures and diesel particulate matter, and for PM2.5, PM10, and NO2, with less consistently elevated associations for NO, ozone, and CO.

“Results for the included studies showed elevated associations between autism and measures of mixed air pollutant exposures and diesel particulate matter (Fig. 2) and for the individual air pollutants PM2.5, PM10, and NO2, with less consistently elevated associations for NO, ozone, and CO (Fig. 3).”

May combine two claims.

The size of ORs was not consistent across studies despite standardized comparison, for example ORs were around 1.5 per 10 ppb increase in NO2 for the California CHARGE study but only 1.04 for the California Department of Developmental Services study.

“The size of the ORs was not consistent across studies, despite the standardized comparison of air pollutant concentrations that we calculated, for example, ORs were around 1.5 per 10 ppb increase in NO2 for the California CHARGE study (Fig. 3, red),72 but only 1.04 for the California Department of Developmental Services study (Fig. 3, green).73”

• cites [72] Volk, 2013, Traffic-related air pollution, particulate matter, and autism, J Am Med Assoc PsychiatryNot checked yet

  Not checked in the free run.

• cites [73] Becerra, 2012, Ambient air pollution and autism in Los Angeles County, California, Environ Health Perspect sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Across metal studies, results were predominantly above the null, consistent with either metal risk or residual confounding, though confounding was not highly likely because studies adjusted for socioeconomic status and maternal age.

“Across all metals in these studies, results were predominantly above the null, a pattern consistent with either higher risk due to metal exposure or consistent residual confounding across designs, confounding not highly likely given that all of these studies adjusted for socioeconomic status and maternal age, but possible”

• AssumptionRests on an assumption: Adjustment for socioeconomic status and maternal age is sufficient to make residual confounding an unlikely explanation for the metal-autism associations.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Chromium and nickel odds ratios were consistent in magnitude across studies; meta-analysis would improve precision and resolve elevated associations.

“For the metals chromium and nickel, the ORs were of consistent magnitude across studies, although the exposure concentration comparisons differed somewhat; if combined in a meta-analysis, the expectation would be that precision would improve, resolving elevated associations”

May combine two claims.

In one study, lead and manganese appeared inversely related to autism risk, possibly due to a stronger association in the speech and language impairment comparison group.

“In one study, lead, and, to a lesser extent, manganese, appeared inversely related to autism risk, which could have been caused by a stronger association with the comparison group in this design: children with speech and language impairment”

• cites [16] Kalkbrenner, 2010, Perinatal exposure to hazardous air pollutants and autism spectrum disorders at age 8, Epidemiology sourceNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: The comparison group of children with speech and language impairment in one metal study may have a stronger association with lead or manganese, causing inverse findings.

May combine two claims.

No studies addressed arsenic in drinking water or lead from house dust and soil ingestion.

“no studies addressed the most common source of arsenic: drinking water, and no studies addressed lead exposure from ingestion of items contaminated with house dust and soil”

May combine two claims.

For all but two thimerosal-autism associations, results were most consistent with chance, with small odds ratios, above and below the null, and confidence intervals spanning the null, suggesting no increased risk.

“For all but two of the associations between thimerosal and autism, results were most consistent with a pattern due to chance, demonstrated by ORs of small magnitude (most between 0.9 and 1.2), above and below the null, and with confidence intervals spanning the null, suggesting that thimerosal does not increase autism risk”

• AssumptionRests on an assumption: A pattern of small odds ratios around the null with confidence intervals spanning the null indicates no causal association for thimerosal.

May combine two claims.

The pesticide studies generally supported elevated autism risk with pesticide exposure, with most estimates above the null and many precise enough to rule out sampling error.

“These studies generally supported an association with elevated risk of autism with pesticide exposure, with most point estimates above the null, many with large enough impacts and statistical precision to rule out sampling error”

May combine two claims.

One study suggested early pregnancy susceptibility, but this did not hold in other studies and requires confirmation.

“A period of susceptibility in early pregnancy was suggested by one study, but this trend did not hold in other studies and requires confirmation.”

May combine two claims.

Many pesticides have not been studied for autism, though most cause neurotoxicity.

“many pesticides have not been studied in relation to autism, though most give rise to neurotoxicity”

• cites [143] Roberts, 2012, Pesticide exposure in children, Pediatrics sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Elevated pesticide associations occurred across OC, OP, and other pesticide classes and across agricultural drift, pet treatments, and dietary biomarkers.

“Elevated associations were not limited to one pesticide class, but were found for OC, OP, and other types of pesticides, and were not limited to one exposure route, but seen across studies addressing agricultural drift, use of flea/tick pet treatments, and dietary sources as reflected by biomarkers”

May combine two claims.

It remains difficult to define a discrete autism disorder based on a shared causal pathway, and the relevant variables are unknown.

“However, defining a discrete disorder that reflects a common causal pathway remains elusive. The defining variables are not known.”

May combine two claims.

Many chemicals remain unstudied; they are commonly detected in people and have animal or mechanistic evidence for endocrine, immune, epigenetic, and other pathways that might contribute to autism.

“The number of chemicals not yet studied is large—chemicals that are widely detectable in humans and have animal or mechanistic evidence of the endocrine, immune, epigenetic, and other pathophysiologies that may be involved in causing autism.”

May combine two claims.

Recent larger studies indicate a smaller genetic heritability of autism than earlier studies, which supports an equally strong role for environmental risk factors.

“While initial studies suggested a strong genetic heritability of autism, recent studies with larger sample sizes have demonstrated a lesser influence, including a study of over 14,000 children with autism in Sweden that demonstrated a heritability of 50%, supporting an equally strong role for environmental risk factors.6”

• cites [6] Sandin, 2014, The familial risk of autism, J Am Med Assoc sourceNot checked yet

  Not checked in the free run.

May combine two claims.

When studies include an individual measure of autism, proper confounding control is possible and they are not subject to the ecological fallacy.

“when these studies include an individual measure of autism, proper confounding control is possible and they are not subject to the ecological fallacy.”

• AssumptionRests on an assumption: Community-level exposure estimates are reasonable proxies for individual-level exposure.

Probably not a substantial claim: may not pass S3 (load-bearing).

A 2013 representative U.S. NHANES sample detected 250 xenobiotic chemicals in biological samples.

“250 xenobiotic chemicals were detected in biological samples from a 2013 representative sample of the U.S. in the National Health and Nutrition Examination Survey.12”

• cites [12] US Department of Health and Human Services. Fourth National Report on Human Exposure to Environmental Chemicals, Updated Tables. Available at: http://www.cdc.gov/exposurereport/pdf/FourthReport_UpdatedTables_Sep2013.pdf; 2013 Accessed 16.12.13.Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

Because all children are tested in continuous autism phenotype studies, an outside comparison group is not needed.

“all children are tested and so an outside comparison group is not needed”

May combine two claims.

Of more than 80,000 chemicals, over 1,000 have laboratory evidence of neurotoxicity, but only a small fraction have been studied in humans during critical developmental windows.

“out of a chemical universe topping 80,000 agents, over 1000 have laboratory evidence of neurotoxicity, but only a small fraction have been studied in humans during critical windows of development.10,11”

• cites [10] Grandjean, 2006, Developmental neurotoxicity of industrial chemicals, Lancet sourceNot checked yet

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• cites [11] Grandjean, 2014, Neurobehavioural effects of developmental toxicity, Lancet Neurol sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based).

The psychometric autism screening tests used in the included studies have been validated.

“We have included these studies because the psychometric autism screening tests used have been validated”

May combine two claims.

Ecological studies cannot establish that the exposed individual is the same as the diagnosed individual and cannot account for individual-level confounding.

“In aggregate outcome data, it cannot be known that the individual experiencing the exposure is the same individual within the group that had an autism diagnosis. Furthermore, it is not possible to account for individual-level confounding influences in this type of design”

• cites [17] Greenland, 1994, Invited commentary: ecologic studies—biases, misconceptions, and counterexamples, Am J Epidemiol sourceNot checked yet

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• cites [18] Braun, 2009, Autism prevalence and precipitation: the potential for cross-level bias, Arch Pediatr Adolesc Med sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Continuous autism phenotype measures in a general population differ from clinical diagnoses because fewer children show symptoms at the upper extreme and the behavioral traits measured may differ.

“Measures of the continuous autism phenotype in a general population differ from clinical diagnoses because fewer study children will exhibit symptoms at the upper extreme that would lead to an autism diagnosis, and because the behavioral traits measured may differ from the constructs that led a clinician to diagnose autism.”

May combine two claims.

Controlled laboratory animal studies cannot directly address the full spectrum of autism or the real-world human living condition.

“Findings from controlled laboratory studies on other animals are important in elucidating mechanisms, screening many exposures, and creating highly controlled conditions that strengthen causal inference, but cannot directly address the full spectrum of autism or the real-world human living condition.”

Classified as probably not a substantial claim. May combine two claims.

Poor precision was defined as a confidence interval ratio or difference greater than 10, arising when fewer than five children with autism had the xenobiotic exposure, a commonly used criterion of insufficient sample size.

“We have excluded some estimates with poor precision, which we defined as estimates with a confidence interval ratio or difference (upper 95% CI divided by, for ORs, or with a subtraction of, for slopes, the lower 95% CI) >10. These estimates arose when fewer than five children with autism had the xenobiotic exposure, a commonly used criterion of insufficient sample size.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Metals in hair during childhood may indicate altered metal metabolism or clearance, or altered diet or medication use, any of which could result from autism rather than contribute to its development.

“metals in hair during childhood may indicate altered metal metabolism and clearance, or altered diet or medication use, any of which could result from autism, instead of contributing to the development of autism.”

Classified as probably not a substantial claim.

Study estimates with greater precision contribute more strongly to accumulated evidence, for example by carrying more weight in a meta-analysis.

“Study estimates that have greater precision (more narrow confidence intervals) contribute more strongly to the accumulated evidence, for example, they carry more weight when included in a meta-analysis.”

May combine two claims.

Disadvantaged racial/ethnic or sociodemographic groups have lower rates of autism diagnosis, and up to 20% of children are not diagnosed by 8 years of age.

“disadvantaged racial/ethnic or sociodemographic groups have been shown to have lower rates of diagnosis1,29 and up to 20% of children are not diagnosed by 8 years of age,1”

• cites [1] Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators, 2014, Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2010, MMWR Surveill SummNot checked yet

  Not checked in the free run.

• cites [29] Mandell, 2009, Racial/ethnic disparities in the identification of children with autism spectrum disorders, Am J Public Health sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Molecular and pathological evidence implicates later pregnancy and early postnatal life, pointing to altered neuronal connectivity and signaling pathways under intense development in these periods.

“Later pregnancy and early postnatal life are additionally implicated by accumulating molecular and pathological evidence pointing to altered neuronal connectivity and a resultant perturbation in signaling pathways, systems under intense development in these periods.25,26”

• cites [25] Stamou, 2013, Neuronal connectivity as a convergent target of gene×environment interactions that confer risk for Autism Spectrum Disorders, Neurotoxicol Teratol sourceNot checked yet

  Not checked in the free run.

• cites [26] Levitt, 2009, The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders, J Clin Invest sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Tobacco use in pregnancy measured by parent recall is subject to under-reporting because of stigma, and medical data collected prospectively is considered reasonably valid for in utero tobacco exposure but still subject to under-reporting.

“Tobacco use in pregnancy was measured by parent recall, which is subject to some degree of under-reporting because of stigma, and by medical data (e.g., birth certificates) that was collected prospectively and considered reasonably valid for measuring in utero tobacco exposure,50 but was still subject to under-reporting.36”

• cites [50] Vinikoor, 2010, Reliability of variables on the North Carolina birth certificate: a comparison with directly queried values from a cohort study, Paediatr Perinat Epidemiol sourceNot checked yet

  Not checked in the free run.

• cites [36] Dietz, 2011, Estimates of nondisclosure of cigarette smoking among pregnant and nonpregnant women of reproductive age in the United States, Am J Epidemiol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Limiting the review to exposures during conception, pregnancy, and the first postnatal year ensures that environmental chemical exposures occurred before autism symptoms and could not result from autism sequelae.

“By limiting to exposures pertaining to these periods, it is assured that the environmental chemical exposures occurred prior to the development of autism symptoms and could not result from the sequelae of autism.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Sampling error is an alternate explanation for an elevated or reduced association and is often ruled out using standard statistical testing and p values.

“An alternate explanation of an elevated (or reduced) measure of association between an environmental chemical and autism is sampling error, often ruled out using standard statistical testing and p values.”

May combine two claims.

A possible link between maternal smoking and higher-functioning autism was suggested, but it is complicated by sociodemographic confounding and phenotypic overlap with other neurodevelopmental disabilities.

“A possible link with higher-functioning autism was suggested, but complicated by sociodemographic confounding and the phenotypic overlap with other neurodevelopmental disabilities.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Women who continue to smoke when pregnant may be genetically predisposed toward addictive behavior, which may pass along increased genetic loading for neuropathologies related to autism risk, complicating the study of tobacco and neurodevelopment.

“Women who continue to smoke when pregnant may be genetically predisposed toward addictive behavior, which in turn may pass along increased genetic loading for neuropathologies that are related to autism risk (e.g., through dopamine or serotonin pathways), complicating the study of tobacco and neurodevelopment.”

• cites [59] Tran, 2013, Smoking during pregnancy and risk of autism spectrum disorder in a Finnish national birth cohort: smoking during pregnancy and risk of autism, Paediatr Perinat Epidemiol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Levels of some air pollutants have declined in the U.S. because of the Clean Air Act and vehicle emissions standards, but concerns remain because the developmental impacts of current ambient levels have not been adequately studied.

“Although levels of some air pollutants have declined in the U.S. because of the Clean Air Act and vehicle emissions standards, these declines have not put an end to concerns about the health impacts of air pollutants, in part because the developmental impacts of current levels of ambient air pollutants have not been adequately studied.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Air pollutants enter the human body via inhalation and by direct translocation from the nose to the brain via the olfactory bulb.

“Air pollutants enter the human body via inhalation and by direct translocation from the nose to the brain via the olfactory bulb.65”

• cites [65] Oberdörster, 2004, Translocation of inhaled ultrafine particles to the brain, Inhal Toxicol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The country pattern may reflect different practices of autism screening and health services access between the U.S. and Scandinavian countries, and this hypothesis has direct data support.

“These patterns may reflect different practices of autism screening and health services access between the U.S. vs. Scandinavian countries, and this hypothesis has direct data support.60”

• cites [60] Rai, 2012, Parental socioeconomic status and risk of offspring autism spectrum disorders in a Swedish population-based study, J Am Acad Child Adolesc Psychiatry sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Secondhand smoke is a different chemical mixture than primary smoke, has evidence of neurodevelopmental toxicity, and is a very common exposure.

“secondhand smoke is a different chemical mixture than primary smoke, (2) there is evidence that secondhand smoke exhibits neurodevelopmental toxicity,61,62 and (3) it is a very common exposure.”

• cites [61] Liu, 2013, Mother׳s environmental tobacco smoke exposure during pregnancy and externalizing behavior problems in children, Neurotoxicology sourceNot checked yet

  Not checked in the free run.

• cites [62] Chen, 2013, Is exposure to secondhand smoke associated with cognitive parameters of children and adolescents?—a systematic literature review, Ann Epidemiol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Season of birth is an important potential confounder because autism occurrence varies by season of conception for unknown reasons and criteria air pollutant concentrations have strong seasonal gradients, so an observed association may reflect another seasonal risk factor.

“Season of birth is also an important potential confounder because the occurrence of autism varies by season of conception for unknown reasons, and because criteria air pollutant concentrations exhibit strong seasonal gradients, so that an observed association between an air pollutant and autism may actually reflect another seasonal risk factor”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Smaller particulate pollutants penetrate more deeply into the lungs and have greater surface area, increasing their biological activity.

“Smaller particulate pollutants penetrate more deeply into the lungs than larger particulates and have greater surface area, increasing their biological activity.”

May combine two claims.

Included air pollution studies had adequate sample sizes ranging from 284 to 7594 children with autism and controlled for confounders such as maternal age and parents' education.

“The studies had adequate sample sizes (ranging from 284 to 7594 children with autism) and controlled for appropriate confounders such as maternal age and parents’ education level.”

May combine two claims.

Spatial patterns of air pollutant exposures coincide with other drivers of autism occurrence and detection, necessitating strong control of socioeconomic confounding.

“The spatial patterns of air pollutant exposures coincide with other drivers of autism occurrence and detection, necessitating the strong control of socioeconomic confounding for questions about air pollutants and autism.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Season of birth was accounted for in one included study.

“Season of birth was accounted for in one of the included studies.74”

• cites [74] Kalkbrenner, 2013, Exposure to ambient coarse particulate matter by gestational period and autism spectrum disorders in North Carolina and California, Am J EpidemiolNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

It is possible that associations observed between autism and traffic air pollutants could be due wholly or in part to traffic noise, although one attempt to adjust for noise in studies of traffic pollution has not borne this out.

“It is possible that associations observed between autism and air pollutants from traffic could be due wholly or in part to traffic noise, although one attempt to adjust for noise in studies of traffic pollution has not borne this out.76”

• cites [76] Guxens, 2012, Prenatal exposure to residential air pollution and infant mental development: modulation by antioxidants and detoxification factors, Environ Health Perspect sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Traffic noise was not explored as a potential confounder in any included study; noise can cause stress, interfere with sleep, and has been associated with cognitive performance.

“One potential confounding influence was not explored in any study: that of noise due to traffic. Noise can cause a stress response or interfere with sleep and has been associated with cognitive performance.75”

• cites [75] Clark, 2007, The effect of transportation noise on health and cognitive development: a review of recent evidence, Int J Comp Psychol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Fetuses can be exposed to chemical constituents of air pollutants and to elevated levels of inflammatory cytokines or other resultant biologic factors in maternal circulation.

“Fetuses can be exposed to the chemical constituents of the air pollutant itself (e.g., metals) and also to the elevated levels of inflammatory cytokines (or other resultant biologic factors) in the maternal circulation.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Air pollution exposures are widespread; urban areas are hotspots, but rural areas can also have high levels near factories and waste incineration facilities.

“Air pollution exposures are widespread. While urban areas are hotspots for air pollutant mixtures—given that air pollutants arise from traffic and population density—rural areas can also have high levels of air pollutants when they are close to factories, waste incineration facilities, and the like.”

May combine two claims.

Some air pollutants induce oxidative stress and cause a systemic inflammatory reaction, a proposed mechanism whereby air pollutant exposures may perturb neurodevelopment.

“Some air pollutants are known to induce oxidative stress and cause a systemic inflammatory reaction, a proposed mechanism whereby air pollutant exposures may perturb neurodevelopment.66–68”

• cites [66] Levesque, 2011, Diesel exhaust activates and primes microglia: air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity, Environ Health Perspect sourceNot checked yet

  Not checked in the free run.

• cites [67] Calderón-Garcidueñas, 2011, Exposure to severe urban air pollution influences cognitive outcomes, brain volume and systemic inflammation in clinically healthy children, Brain Cogn sourceNot checked yet

  Not checked in the free run.

• cites [68] Sunyer, 2008, The neurological effects of air pollution in children, Eur Respir J sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The air pollution findings are supported by strong study designs and consistency across pollutant measurement and autism identification methods.

“These findings are bolstered by strong study designs and consistent findings across different means of measuring pollutant concentration and identifying children with autism.”

May combine two claims.

Lead and mercury have strong consistent evidence of harming the developing nervous system, causing IQ loss and behavioral problems.

“Lead and mercury have strong and consistent evidence of harming the developing nervous system, resulting in impairments such as the loss of IQ points and behavioral problems.”

• cites [42] Mendola, 2002, Environmental factors associated with a spectrum of neurodevelopmental deficits, Ment Retard Dev Disabil Res Rev sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

VOCs are ubiquitous and occur together with other VOCs and pollutants.

“VOCs are ubiquitous and occur in combination with other VOCs and pollutants covered elsewhere in this review”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The primary VOC exposure route is inhalation, with ingestion and dermal absorption also possible.

“The primary route of exposure to VOCs is by inhalation, although VOCs can be ingested through contaminated drinking water and can be dermally absorbed.”

• cites [81] Brown, 1984, The role of skin absorption as a route of exposure for volatile organic compounds (VOCs) in drinking water, Am J Public Health sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Because VOC half-lives range from minutes to days, detected body burdens indicate frequent exposure.

“the biological half-lives of VOCs range from minutes to days, indicating frequent exposure to these chemicals”

May combine two claims.

VOC studies, though underpowered and with measurement error, show patterns suggestive of causal associations for certain VOCs.

“studies of VOCs and autism, despite being underpowered with some degree of exposure measurement error, have shown patterns suggestive of causal associations that point to the need for more research on certain VOCs”

May combine two claims.

Other VOCs are not exonerated but have not been adequately studied.

“Other VOCs are not cleared from culpability, but instead have simply not been adequately studied.”

Probably not a substantial claim: may not pass S3 (load-bearing).

VOC concentrations are generally two to five times higher indoors than outdoors.

“VOC concentrations are generally 2–5 times higher in indoor compared to outdoor air”

• cites [78] Wang, 2007, Volatile organic compounds in indoor environment and photocatalytic oxidation: state of the art, Environ Int sourceNot checked yet

  Not checked in the free run.

• cites [79] Payne-Sturges, 2004, Personal exposure meets risk assessment: a comparison of measured and modeled exposures and risks in an urban community, Environ Health Perspect sourceNot checked yet

  Not checked in the free run.

May combine two claims.

VOCs affect multiple organ systems including the nervous system, with rat evidence of neurodevelopmental toxicity.

“VOCs interact with many organ systems, including the nervous system, as demonstrated by evidence in rats of neurodevelopmental toxicity.”

• cites [83] Gospe, 1998, Toluene abuse embryopathy: longitudinal neurodevelopmental effects of prenatal exposure to toluene in rats, Reprod Toxicol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

VOC harm mechanisms include oxidative stress after P450 metabolism and membrane disruption by lipophilic VOCs.

“Biologic mechanisms of harm include oxidative stress after metabolism by P450 enzymes and direct interference with cell membrane integrity for the many VOCs that are lipophilic.”

• cites [82] Barr, 2014, Volatile organic compoundsNot checked yet

  Not checked in the free run.

May combine two claims.

Thimerosal contains ethylmercury, considered less toxic than methylmercury.

“Thimerosal contains ethylmercury, considered a less toxic form of mercury compared to methylmercury.”

• cites [99] Clarkson, 2003, The toxicology of mercury—current exposures and clinical manifestations, N Engl J Med sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Arsenic occurs in contaminated drinking water from arsenical soil in some U.S. areas, with secondary sources including treated wood, pesticides, and diet.

“Arsenic is found in contaminated drinking water resulting from arsenical soil, including in some parts of the U.S., with secondary sources including arsenic-treated wood, arsenic-containing pesticides, and some dietary sources”

May combine two claims.

Metals cross the placenta and blood-brain barrier, accumulate in developing brains, and act at the cellular level via receptor interference and reactive oxygen species.

“Metals cross the placenta and the blood–brain barrier, accumulate in developing brains, and interact directly at the cellular level through a variety of mechanisms, including interfering with key cellular receptors and causing reactive oxygen species.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A possible reason for the null Seychelles result is that fish nutrients counteracted mercury toxicity.

“One possible reason for the lack of observed elevated association in the Seychelles study is that mercury exposure was almost entirely from fish consumption in this population, so that the impacts of brain-enhancing nutrients contained in fish may have counteracted any toxic impact of mercury.”

• AssumptionRests on an assumption: Beneficial nutrients in fish can counteract mercury toxicity enough to explain the null Seychelles result.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Persistent chemicals like mercury are lipophilic and not readily broken down, concentrating in predatory fish and human milk.

“Persistent environmental chemicals like mercury often have affinity for fatty tissues (they are lipophilic) and so are not readily broken down. After widespread use and distribution, such chemicals deposit in waterways and concentrate toward the top of the food chain in predatory fish and human milk.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Sociodemographic and neighborhood factors are important potential confounders in studies of lead and other metals.

“Sociodemographic and neighborhood factors, therefore, are important potential confounders when studying lead (and other metal) exposures.”

May combine two claims.

Fish containing methylmercury also contain other persistent pollutants and beneficial nutrients, creating negative and positive confounding.

“The same fish that contain methylmercury accumulate other persistent organic pollutants, such as those covered later in this review, and also contain beneficial nutrients (e.g., fatty acids), leading to problems of negative and positive confounding from the mixtures of chemicals present in some fish.”

May combine two claims.

Most metal studies examined less important exposure routes such as air, so they likely underestimate the full metal impact.

“The other studies only pertained to less important routes of metal exposure (e.g., air), and so are unlikely to represent the full impact of these metals on autism risk.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Methylmercury exposure occurs primarily through diet because it bioaccumulates.

“Mercury exposure, especially the most toxic form, methylmercury, occurs primarily from diet, because it bioaccumulates in the environment.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Dental amalgams and outdoor air near coal combustion are less important mercury sources.

“Less important sources of mercury exposure include dental amalgams (during placement and from continual release of trace amounts of mercury vapor for the life of the amalgam) and outside air near coal combustion and some industrial facilities.”

May combine two claims.

Existing metal studies suggest metal exposure may cause autism but are limited in scope.

“the existing studies of autism due to metals from air, occupation, dental amalgams, and diet are suggestive that metal exposure may cause autism but are, for the most part, limited in scope”

May combine two claims.

Pesticide exposure is widespread: OC pesticides were detected in over 97% and OP metabolites in 70% of U.S. biosamples.

“in a representative sample in the U.S., OC pesticides were detected in over 97% of bio-samples, while OP pesticide metabolites were detected in 70%”

• cites [12] US Department of Health and Human Services. Fourth National Report on Human Exposure to Environmental Chemicals, Updated Tables. Available at: http://www.cdc.gov/exposurereport/pdf/FourthReport_UpdatedTables_Sep2013.pdf; 2013 Accessed 16.12.13.Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The MMR vaccine never contained thimerosal and is outside the review's scope.

“measles, mumps, and rubella (MMR) vaccine, which never contained thimerosal and so is outside the scope of this review”

May combine two claims.

The public health importance of thimerosal has diminished because it was removed from pediatric vaccines, though pregnant women may still receive thimerosal-containing influenza vaccines.

“The public health importance of this controversial issue has diminished given the prophylactic removal of thimerosal from pediatric vaccines, although pregnant women may still receive thimerosal-containing influenza vaccines.”

May combine two claims.

Although included thimerosal studies met validity criteria, minor flaws may have attenuated observed odds ratios.

“Although the studies we included met our validity criteria, some minor flaws may have created such an influence.”

• AssumptionRests on an assumption: The included thimerosal studies' validity criteria are adequate to support the conclusion of no association despite minor flaws.

May combine two claims.

Currently only some influenza vaccines contain more than trace thimerosal, and infants and pregnant women may be exposed.

“Currently, the only vaccines containing more than trace amounts of thimerosal are some influenza vaccines, to which both infants and pregnant women may be exposed.”

• cites [100] U.S. Food and Drug Administration. Thimerosal in Vaccines. Table 3. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/UCM096228#t1; updated June 20, 2012. Accessed 28.3.14.Not checked yet

  Not checked in the free run.

May combine two claims.

Pesticides can cross the placenta and blood-brain barrier.

“Pesticides can pass through the placenta and the blood–brain barrier.”

• cites [113] Bradman, 2003, Measurement of pesticides and other toxicants in amniotic fluid as a potential biomarker of prenatal exposure: a validation study, Environ Health Perspect sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Over 600 unique chemical pesticides and 20,000 commercial products are on the market, with over one billion pounds used annually in the U.S.

“Over 600 unique chemical pesticides and 20,000 commercial pesticide products, categorized by function as insecticide, herbicide, fungicide, rodenticide, fumigant, and repellant, are on the market, and over one billion pounds are used in the U.S. each year.”

• cites [111] Karr, 2014, PesticidesNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Healthier babies may receive vaccines earlier and be less likely to develop autism, potentially creating an artificial inverse association.

“the healthiest babies may be given vaccines earlier, and may be independently less likely to develop autism, possibly leading to an artificial influence where earlier vaccines are associated with less autism”

• cites [15] Hertz-Picciotto, 2011, Environmental risk factors in autism: results from large-scale epidemiologic studiesNot checked yet

  Not checked in the free run.

May combine two claims.

None of the pesticide studies adjusted for other agricultural exposures, so observed associations might reflect another co-occurring chemical.

“none adjusted for other agricultural exposures, and it is therefore possible that observed associations between pesticides and autism may, in actuality, be reflecting a causal influence of another chemical along for the ride”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

PBDEs and PFCs are currently used chemicals.

“Currently used chemicals include polybrominated diphenyl ethers (PBDEs, used as flame-retardant additives to textiles and plastic casings of electronics) and perfluorinated compounds (PFCs, used as non-stick coatings in cookware and outdoor gear).”

May combine two claims.

The seven included pesticide studies had reliable autism diagnosis, suitable controls with limited selection bias, and adjusted for social class and maternal age.

“All of these studies exhibited reliable information on autism diagnosis or characteristics, used suitable controls with limited selection bias, and accounted for important confounders such as social class and maternal age.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Persistent organic pollutants are synthetic carbon-based chemicals that accumulate in the environment and human tissues.

“Persistent organic pollutants are synthetic, carbon-based chemicals that accumulate in the environment and in human tissues”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The Stockholm Convention banned PCBs and some dioxins including TCDD.

“Persistent organic pollutants that were banned by the Stockholm Convention in 2001 include PCBs (heat-stable lubricants used throughout industry) and some dioxins (such as 2,3,7,8-tetrachlorodibenzodioxin, TCDD”

• cites [144] Patterson, 2009, Levels in the U.S. population of those persistent organic pollutants (2003−2004) included in the Stockholm Convention or in other long-range transboundary air pollution agreements, Environ Sci Technol sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Some OC pesticides persist and remain detectable decades after bans, such as DDT.

“OC pesticides are persistent pollutants and some are detectable in the environment and human tissues decades after they have been banned, such as the OC pesticide DDT.”

• cites [128] Xu, 2010, Associations of serum concentrations of organochlorine pesticides with breast cancer and prostate cancer in U.S. adults, Environ Health Perspect sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In one largely Hispanic agricultural study, the pesticide-autism association may have been overestimated due to psychometric test performance and use of an odds ratio for a common outcome.

“In one study among a largely Hispanic, agricultural community, the association between pesticides and autism may have been overestimated because of unusual performance of the psychometric test in this population and because the study used an OR, which is best suited for rare diseases, for a common outcome.”

• cites [15] Hertz-Picciotto, 2011, Environmental risk factors in autism: results from large-scale epidemiologic studiesNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: Autism is common enough that using an odds ratio may overestimate association in one pesticide study.

May combine two claims.

Co-pollutant confounding is not likely to be large because pesticides have demonstrated neurotoxicity and studies used different methods and settings.

“this co-pollutant confounding influence is not likely to be large: pesticides are chemicals with demonstrated neurotoxicity and these studies measured pesticides using different methods and across different settings”

May combine two claims.

All included POP studies adjusted for sociodemographic confounders, and all except one adjusted for maternal age.

“All of these studies adjusted for important sociodemographic confounders, and all except for one adjusted for maternal age.”

• cites [58] Larsson, 2009, Associations between indoor environmental factors and parental-reported autistic spectrum disorders in children 6–8 years of age, Neurotoxicology sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Maternal age, birth order, and breast-feeding are important because older mothers accumulated more chemicals and breast-feeding excretes lipophilic chemicals.

“maternal age, because older moms were living in times prior to chemical bans and incurred more years to accumulate body burdens, and birth order and breast-feeding practices, in part because breast-feeding is one of the most effective methods of excreting lipophilic chemicals”

• cites [157] Hardell, 2010, Time trends of persistent organic pollutants in Sweden during 1993–2007 and relation to age, gender, body mass index, breast-feeding and parity, Sci Total Environ sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Phthalate and BPA biomarkers are objective and quantitative, and one study collected them more than once in pregnancy.

“biomarkers of phthalates and BPA have strengths of being objective, quantitative measures, and in one study were collected more than one time in pregnancy”

• cites [136] Braun, 2014, Gestational exposure to endocrine-disrupting chemicals and reciprocal social, repetitive, and stereotypic behaviors in 4- and 5-year-old children: the HOME Study, Environ Health Perspect sourceNot checked yet

  Not checked in the free run.

May combine two claims.

BPA and phthalates are non-persistent but exposure is ubiquitous and continuous, so chronic effects are important to examine.

“Although these chemicals are not persistent, that is, they are readily cleared from the human body in part because they are water soluble, exposure is ubiquitous and continuous, so is important to examine for chronic effects.”

May combine two claims.

Other mechanisms of these organic pollutants include neurotoxicity and immunotoxicity.

“Other pathophysiological mechanisms of these organic pollutants include neurotoxicity or immunotoxicity.”

• cites [147] Hertz-Picciotto, 2008, Prenatal exposures to persistent and non-persistent organic compounds and effects on immune system development: prenatal exposures and immune development, Basic Clin Pharmacol Toxicol sourceNot checked yet

  Not checked in the free run.

• cites [148] Kajta, 2013, Impact of endocrine-disrupting chemicals on neural development and the onset of neurological disorders, Pharmacol Rep sourceNot checked yet

  Not checked in the free run.

• cites [149] Landrigan, 2014, Polychlorinated biphenyls, dioxins, furans, DDT, polybrominated compounds, polyfluorinated compounds, and other halogenated hydrocarbonsNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

PBDE dust biomarker levels are especially high in California where flammability standards were stricter.

“dust biomarker levels are especially high in California, where flammability standards had until recently been more strict than in the U.S. as a whole”

• cites [155] Zota, 2008, Elevated house dust and serum concentrations of PBDEs in California: unintended consequences of furniture flammability standards?, Environ Sci Technol sourceNot checked yet

  Not checked in the free run.

May combine two claims.

PBDEs are structurally similar to thyroid hormone, which is required during discrete neurodevelopmental periods.

“PBDEs are structurally similar to thyroid hormone, which is required during discrete periods of neurodevelopment.”

• cites [146] Messer, 2010, Mini-review: polybrominated diphenyl ether (PBDE) flame retardants as potential autism risk factors, Physiol Behav sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Because exposure measurement is difficult, especially for short-half-life phthalates and BPA, none of these chemicals can be ruled out as causes of neurodevelopmental harm.

“Given the difficulty in measuring exposure, especially for phthalates and BPA, which have short half-lives, it is not possible to rule out any of these chemicals from causing neurodevelopmental harm.”

May combine two claims.

Male sex is among the strongest predictors of an autism diagnosis, particularly higher-functioning autism.

“Being a male is one of the strongest predictors of being diagnosed with autism, especially higher-functioning autism”

• cites [159] Baron-Cohen, 2010, Empathizing, systemizing, and the extreme male brain theory of autism, Prog Brain Res sourceNot checked yet

  Not checked in the free run.

• cites [160] Cheslack-Postava, 2012, Autism spectrum disorders: toward a gendered embodiment model, Soc Sci Med sourceNot checked yet

  Not checked in the free run.

• cites [161] Lai, 2013, Biological sex affects the neurobiology of autism, Brain J Neurol sourceNot checked yet

  Not checked in the free run.

• cites [162] Schaafsma, 2014, Etiologies underlying sex differences in autism spectrum disorders, Front Neuroendocrinol sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

If epigenetic transgenerational effects matter, current studies may miss relevant parental or grandparental exposures.

“if transgenerational impacts are implicated via epigenetic mechanisms, these studies may completely miss the relevant exposures that occurred for parents or grandparents”

Classified as probably not a substantial claim.

Studies to date have focused on the prenatal period.

“Studies to date have focused on the important prenatal period”

Probably not a substantial claim: may not pass S2 (checkable).

Asking whether environmental exposures as a whole cause autism is inadequate for guiding primary prevention.

“the question about whether environmental exposures/compounds, as a whole, cause autism, is not sufficient to guide the primary prevention of autism.”

• AssumptionRests on an assumption: The environment is not a single entity.

May combine two claims.

Genetic polymorphisms of possible relevance include those involved in xenobiotic metabolism or activation, those allowing improved resiliency to neurodevelopmental damage, and those conferring autism risk that combined with xenobiotic damage result in autism.

“Genetic polymorphisms of possible relevance include those encoding proteins involved in the metabolism or biological activation of the xenobiotic, genes allowing improved resiliency to neurodevelopmental damages, or genes that confer some degree of autism risk that, when combined with xenobiotic damage, result in autism.”

May combine two claims.

The strong child sex-autism association creates a research challenge: females with autism are much fewer than males, which limits power to test sex-by-environment interactions.

“The very strength of the child sex-autism association presents a research challenge because the number of females with autism in any given study will be much smaller than the number of males, limiting the statistical power to assess sex × environment interactions.”

Classified as probably not a substantial claim.

Autism is one expression of developmental neurological damage within a wider group of neurodevelopmental conditions that also includes cognitive impairment, attention-deficit disorders, and sensory processing disorders.

“autism is one manifestation of developmental neurological damage, part of the broader set of neurodevelopmental problems including cognitive impairments, attention-deficit disorders, sensory processing disorders, and more.”

• AssumptionRests on an assumption: Children given autism diagnoses vary widely in symptoms, disability level, and co-occurring conditions.

May combine two claims.

Different exposure-specific critical windows are unsurprising because chemicals have varied biological actions and neurodevelopment involves many interacting events pre- and postnatally that could produce autism symptoms if disrupted.

“Different critical windows for different exposures is not unexpected given the various biological activities of environmental chemicals and the many, interwoven events of neurodevelopment, taking place during pregnancy and postnatal life, which, if disrupted, could manifest in autism symptoms.”