Autism's environmental causes: Philip Landrigan's flawed review

Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
March 06, 2010

"What causes autism? Exploring the environmental contribution"

That's the title of Philip J. Landrigan's recently published review (1).  That such an essay (see also 2) would be presented in Current Opinion in Pediatrics is a step in the right direction even as major flaws in Dr. Landrigan's review merit attention.

: Current Opinion in Pediatrics is among the journals that promote vaccinations (eg, 3-6) and that endorse recommendations of the CDC's Advisory Committee on Immunization Practices (ACIP; eg, 4,6,7). Caution is warranted.

For instance, the ACIP recently recommended flu shots for the elderly (8) despite a major Cochrane Database review which found that existing data do not imply that influenza vaccinations for the elderly are efficacious (9). Similarly, Current Opinion in Pediatrics and the CDC's ACIP endorse Gardasil vaccinations (5, 12), despite well-documented reports of adverse effects (eg, 9-13).

That Current Opinion in Pediatrics represents individuals and corporations who profit from vaccinations may have shaped Dr. Landrigan's review in at least two ways. Firstly, his review offers prenatal timing as virtually the only possible time for disruption of neurodevelopment in ways inducing autism or one of the other autism-spectrum disorders (ASDs). Secondly, his review offers as quasi-sacred truth that "There is no credible evidence that vaccines cause autism" - despite a growing body of evidence that vaccinations induce or are associated with autism in some children. Furthermore, whereas Dr. Landrigan calls attention to "thousands of synthetic chemicals", his essay omits peer-reviewed citations (a) documenting autism associations with mercury, arsenic, trichloroethylene, pesticides, etc, and (b) documenting thimerosal's relevance to autism.

: Human neurodevelopment is not limited to in utero timing and continues postnatally. Exposures to pollutants not adequately detoxified would augment neurodevelopmental risk pre- as well as post-natally. Postnatal exposures - including vaccinations - may be etiologically significant in some children and ought not be precluded a priori.

"In humans, synaptogenesis is reported to begin as early as gestation month 2 and continues into postnatal life, with a peak in the first year of life (14, citing 15) and continuing into the human's second year (16). Indeed, late-onset autism has been described (eg, 17). Autism having only in-utero timing, as set forth in Landrigan's review, stands in contrast with late-onset autism, a phenomenon which is at least consistent not only with the timing of autism-symptoms onset (> 6 months old) described by Ozonoff et al (18-19) and but also with parent reports of regression into autism (eg, 20).

Surprisingly but consistent with his preferred rationale, Dr. Landrigan's review doesn't mention Hannah Poling's regression, her late-onset development of autistic traits subsequent to a multiple-vaccinations incident (eg, 21-22).

Clearly, factors etiologically significant in the development of autism can occur postnatally and perceived as regressions. In regard to the timing of autism's causal events, Dr. Landrigan's review is misleading.

Vaccinations and autism: An increasing amount of data indicates that autism and other ASDs are associated with vaccinations, whether the injected biologics contain thimerosal or live-viruses. Nonetheless, the Landrigan review states, "There is no credible evidence that vaccines cause autism." (1) 

His strident rhetoric reflects a dilemma: If scientists find associations between vaccinations and one or more ASDs, those findings are a priori other than credible because they violate preferred principles of orthodox vaccinology. Similarly, if researchers document mechanisms by which thimerosal-containing or live-virus vaccines cause pathologies, then those studies are to be ignored as mainstream researchers omit inculpatory evidence of neurologic and other sequelae while presenting egregiously erroneous statements (as did Landrigan, see quote above in this paragraph).

Although research teams affiliated with vaccine manufacturers or with vaccine-sections of the CDC use study designs that lead to the minimizing or elimination of vaccination-associated adverse-effects findings (eg, 23-25), other researchers report different findings. For instance, thimerosal is associated with autism, other ASDs, and with increased need for special education services (eg, 26-29). Mechanisms of by which thimerosal induces pathologies are described (eg, 30-36).

Similarly for the MMR, some researchers have dared report signals of adverse events related to autism and seizures; and mechanisms of MMR-induced damage are described, including "viral interference" when co-infections occur or multiple live-viruses are injected simultaneously (eg, 37-41; additional cites in 42-43).

Autism-pollutant studies Landrigan omitted: Although Dr. Landrigan mentions "synthetic chemicals", his study omitted autism-pollutant associations already delineated in peer-reviewed articles. Among these associations are mercury from coal-fired power plants, pesticides, trichloroethylene, arsenic, cadmium, vinyl chloride, etc (eg,  44-47).

Clinical significance
: Near the end of his paper, Dr. Landrigan calls for "Toxicological..., Neurobiological, and Prospective epidemiological studies" and mentions the National Children's Study (1). Whereas these are important foci, the Landrigan essay omits already published studies with clinical relevance to pollutants, nutrient status, and detoxification pathways in autistic patients (eg, 48-55). Research into clinicial profiles (see also 56) and pollutant-related treatments has begun and needs be expanded.

: Philip J. Landrigan, M.D., is a respected researcher with decades of experience. Why he chose to omit important studies regarding pollutants and autism and their clinical significance is not known. Why he chose a fictional denial of vaccinations' relevance to autism and other ASDs is more understandable in view of modernity's enforcement of an orthodoxy of vaccinationism. However, although his review seems a welcome addition to autism literature, his essay's omissions sustain misunderstandings regarding the subgroups of infants and toddlers adversely affected by vaccinations and prolongs delay in clinicians' and theoreticians' appreciation for the detoxification of pollutants, whether breathed, injected, or in other ways ingested.


1. What causes autism? Exploring the environmental contribution
Landrigan PJ.
Curr Opin Pediatr. 2010 Jan 16. [Epub ahead of print]

PURPOSE OF REVIEW: Autism is a biologically based disorder of brain development. Genetic factors - mutations, deletions, and copy number variants - are clearly implicated in causation of autism. However, they account for only a small fraction of cases, and do not easily explain key clinical and epidemiological features. This suggests that early environmental exposures also contribute. This review explores this hypothesis. RECENT FINDINGS: Indirect evidence for an environmental contribution to autism comes from studies demonstrating the sensitivity of the developing brain to external exposures such as lead, ethyl alcohol and methyl mercury. But the most powerful proof-of-concept evidence derives from studies specifically linking autism to exposures in early pregnancy - thalidomide, misoprostol, and valproic acid; maternal rubella infection; and the organophosphate insecticide, chlorpyrifos. There is no credible evidence that vaccines cause autism. SUMMARY: Expanded research is needed into environmental causation of autism. Children today are surrounded by thousands of synthetic chemicals. Two hundred of them are neurotoxic in adult humans, and 1000 more in laboratory models. Yet fewer than 20% of high-volume chemicals have been tested for neurodevelopmental toxicity. I propose a targeted discovery strategy focused on suspect chemicals, which combines expanded toxicological screening, neurobiological research and prospective epidemiological studies

Gene-environment interaction and children's health and development
Wright RO, Christiani D.
Curr Opin Pediatr. 2010 Jan 19. [Epub ahead of print]

PURPOSE OF REVIEW: A systematic approach to studying gene-environment interaction can have immediate impact on our understanding of how environmental factors induce developmental disease and toxicity and will provide biological insight for potential treatment and prevention measures. RECENT FINDINGS: Because DNA sequence is static, genetic studies typically are not conducted prospectively. This limits the ability to incorporate environmental data into an analysis, as such data is usually collected cross-sectionally. Prospective environmental data collection could account for the role of critical windows of susceptibility that likely correspond to the expression of specific genes and gene pathways. The use of large-scale genomic platforms to discover genetic variants that modify environmental exposure in conjunction with a-priori planned replication studies would reduce the number of false positive results. SUMMARY: Using a genome-wide approach, combined with prospective longitudinal measures of environmental exposure at critical developmental windows, is the optimal design for gene-environment interaction research. This approach would discover susceptibility variants, and then validate the findings in an independent sample of children. Designs that combine the strengths and methodologies of each field will yield data that can account for both genetic variability and the role of critical developmental windows in the etiology of childhood disease and development.

Immunization updates and challenges
Keeton VF, Chen AK.
Curr Opin Pediatr. 2010 Jan 30. [Epub ahead of print]

PURPOSE OF REVIEW: Childhood vaccination recommendations in the United States have increased throughout the years. Many providers, patients, and families are overwhelmed and have concerns regarding the safety and efficacy of vaccines. Various barriers and challenges exist for healthcare providers to successfully implement the vaccination recommendations. This review will discuss the 2009 and newly released 2010 immunization recommendations, as well as challenges and strategies to improve vaccination in children and adolescents. RECENT FINDINGS: Seasonal influenza immunization continues to be promoted for all children, and recommendations for vaccination against novel influenza A have emerged as well. Concerns surrounding vaccine safety and necessity may cause increasing rates of vaccine refusal among some parents, but clear messages from providers and unbiased information about benefits and risks of immunization may counteract these doubts. Barriers to immunizing adolescents continue as access to healthcare in this age group changes. SUMMARY: Pediatric providers currently face numerous challenges in improving rates of immunization among children and adolescents. Promoting coverage through the influenza vaccines, counseling parents with clear information about the risks and benefits of vaccines, and taking advantage of nonpreventive visits for immunization are some strategies suggested to address these challenges.

Update on universal annual influenza immunization recommendations for children
Bekker A, Chou C, Bernstein HH.
Curr Opin Pediatr. 2009 Feb;21(1):122-6.

PURPOSE OF REVIEW: To provide an update of current recommendations and research findings on universal annual influenza immunization of children. RECENT FINDINGS: The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention and the American Academy of Pediatrics now recommend annual influenza vaccination for all children 6 months through 18 years. New research has examined the effect of 'herd immunity' associated with immunizing all school-aged children, the suboptimal antigenic match between the trivalent vaccine strains and circulating virus strains of last 2007-2008 influenza season, the efficacy of live attenuated influenza vaccine versus trivalent inactivated influenza vaccine, and the tolerance for influenza vaccine in infants less than 6 months of age. With a goal of improving the overall rates of influenza immunization and an eye toward the anticipated increase in volume with expansion of the universal recommendations in children, Advisory Committee on Immunization Practices and American Academy of Pediatrics emphasize the value of extending the timeframe for immunization beyond December and into April, establishing school-based immunization programs and other alternative vaccination sites outside medical homes, and conducting large, population-based studies that examine the overall impact of universal childhood influenza immunization. SUMMARY: Annual influenza vaccination recommendations have been expanded, and research continues on vaccine efficacy, administration, and cost associated with vaccinating all school-aged children.

Human papillomavirus vaccine: a paradigm shift for pediatricians
Jenson HB.
Curr Opin Pediatr. 2009 Feb;21(1):112-21.

PURPOSE OF REVIEW: Recommendations for human papillomavirus (HPV) vaccination during adolescence primarily for a disease, cancer, that occurs only during adulthood is a paradigm shift for pediatricians. Additional postlicensure data and guidelines about HPV biology and epidemiology, disease association, adverse effects, vaccination during pregnancy, and cost-benefit analyses are now available to inform pediatricians and guide HPV vaccination recommendations. RECENT FINDINGS: The prespecified, end-of-study combined analysis of HPV vaccine efficacy studies for prevention of cervical cancer, and now also for prevention of vulvar and vaginal cancers, confirmed 98-100% vaccine efficacy. Postlicensure surveillance identified a new association of vaccine administration with syncope, and provides assurance of the safety of inadvertent vaccination during pregnancy. Several cost-effectiveness analyses consistently demonstrated that HPV vaccination of 12-year-old girls and catch-up vaccination through 18 years of age, and possibly to 26 years of age, is cost-effective, although the thresholds of affordability vary by study. The downward trend in age of initial HPV infection and the need to educate parents and patients about HPV disease and vaccination underscore the essential role of pediatricians in managing HPV illness. SUMMARY: It is critical for pediatricians to thoroughly understand HPV biology and disease and champion HPV vaccination to prevent cervical, vulvar, and vaginal cancers, even though these benefits accrue during adulthood and will likely require 2-4 decades to realize the financial and public health benefits. Several new developments are expected in the near future, including licensure for use in boys and men and the approval of a second, bivalent HPV vaccine.

Update on universal childhood immunizations
Hamlin J, Senthilnathan S, Bernstein HH.
Curr Opin Pediatr. 2008 Aug;20(4):483-9.

PURPOSE OF REVIEW: To provide an update of research findings and recommendations regarding immunizations. RECENT FINDINGS: New research has examined the efficacy of the 2007-2008 influenza vaccine, the transmission and incidence of human papillomavirus, the increased prevalence of pneumococcal serotypes not included in the 7-valent pneumococcal conjugate vaccine, the emergence of a drug-resistant strain of Streptococcus pneumoniae, febrile seizure rates following measles-mumps-rubella-varicella vaccination, and the 2006 mumps outbreak in the American Midwest. The Food and Drug Administration has approved the expansion of live attenuated influenza virus vaccine and quadrivalent meningococcal conjugate vaccine for use in children no younger than 2 years of age. The Advisory Committee on Immunization Practices now recommends immunization with quadrivalent meningococcal conjugate vaccine for all previously unvaccinated 11-18-year-old children and has revised its recommendations for Streptococcus pneumoniae catch-up vaccinations. The Advisory Committee on Immunization Practices no longer expresses a preference for the use of the combination measles-mumps-rubella-varicella vaccine over separate measles-mumps-rubella and varicella administration. Because of a notable recall of Haemophilus influenzae type B vaccines by Merck & Co Inc, Whitehouse Station, New Jersey, USA, the Advisory Committee on Immunization Practices recommends that pediatric providers conserve available Haemophilus influenzae type B vaccines by delaying the administration of the booster dose of the vaccine in healthy children. SUMMARY: New vaccine recommendations continue to be made, and research continues on infectious diseases, vaccine safety, and vaccine efficacy.

The Advisory Committee on Immunization Practices (ACIP)

CDC advisory panel says virtually everyone should get a seasonal flu shot
February 24, 2010 |  4:53 pm

The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommended Wednesday that all Americans over the age of 6 months -- with the exception of those who are allergic to eggs -- should receive a seasonal flu shot every year, beginning this fall. The advice must be accepted by the CDC director and the Department of Health and Human Services before it becomes official, but that ratification is usually pro forma. The CDC has been slowly broadening the recommendations for flu shots over the last few years to the point where about 85% of the population is now covered. The primary exception now is adults ages 19 to 49 who do not have underlying medical conditions. But the committee noted that many such adults do not realize they are at risk because of diabetes, hypertension or other hidden problems and do not seek the shots.

Vaccines for preventing influenza in the elderly
Jefferson T, Di Pietrantonj C, Al-Ansary LA, Ferroni E, Thorning S, Thomas RE.
Vaccines Field, The Cochrane Collaboration, Via Adige 28a, Anguillara Sabazia, Roma, Italy, 00061.
Cochrane Database Syst Rev. 2010 Feb 17;2:CD004876.

BACKGROUND: Vaccines have been the main global weapon to minimise the impact of influenza in the elderly for the last four decades and are recommended worldwide for individuals aged 65 years or older. The primary goal of influenza vaccination in the elderly is to reduce the risk of complications among persons who are most vulnerable. OBJECTIVES: To assess the effectiveness of vaccines in preventing influenza, influenza-like illness (ILI), hospital admissions, complications and mortality in the elderly. To identify and appraise comparative studies evaluating the effects of influenza vaccines in the elderly. To document types and frequency of adverse effects associated with influenza vaccines in the elderly. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register (The Cochrane Library 2009, issue 4); MEDLINE (January 1966 to October Week 1 2009); EMBASE (1974 to October 2009) and Web of Science (1974 to October 2009). SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs, cohort and case-control studies assessing efficacy against influenza (laboratory-confirmed cases) or effectiveness against influenza-like illness (ILI) or safety. Any influenza vaccine given independently, in any dose, preparation or time schedule, compared with placebo or with no intervention was considered. DATA COLLECTION AND ANALYSIS: We grouped reports first according to the setting of the study (community or long-term care facilities) and then by level of viral circulation and vaccine matching. We further stratified by co-administration of pneumococcal polysaccharide vaccine (PPV) and by different types of influenza vaccines. We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications and deaths. MAIN RESULTS: We included 75 studies. Overall we identified 100 data sets. We identified one RCT assessing efficacy and effectiveness. Although this seemed to show an effect against influenza symptoms it was underpowered to detect any effect on complications (1348 participants). The remainder of our evidence base included non-RCTs. Due to the general low quality of non-RCTs and the likely presence of biases, which make interpretation of these data difficult and any firm conclusions potentially misleading, we were unable to reach clear conclusions about the effects of the vaccines in the elderly. AUTHORS' CONCLUSIONS: The available evidence is of poor quality and provides no guidance regarding the safety, efficacy or effectiveness of influenza vaccines for people aged 65 years or older. To resolve the uncertainty, an adequately powered publicly-funded randomised, placebo-controlled trial run over several seasons should be undertaken.

10. A 16-Year-Old Girl With Bilateral Visual Loss and Left Hemiparesis Following an Immunization Against Human Papilloma Virus
Francis J. DiMario, Jr, MD et al.
Journal of Child Neurology, Vol. 25, No. 3, 321-327 (2010)

We report the course of a 16-year-old girl who presented with near complete visual loss associated with chiasmal neuritis and a biopsy proven tumefactive demyelinating lesion on magnetic resonance imaging (MRI) in association with a recent immunization against human papilloma virus.

New Worries About Gardasil Safety
CBS Evening News Exclusive: Vaccine-Safety Group Study Shows Higher Instance Of Medical Side-Effects Than Another Vaccine
By Sharyl Attkisson

Reports of Health Concerns Following HPV Vaccination
CDC  {accessed March 5, 2010}

Judicial Watch Investigates Side-Effects of HPV Vaccine

A model of the development of the brain as a construct of the thyroid system
Howdeshell KL.
Environ Health Perspect. 2002 Jun;110 Suppl 3:337-48.

Neurobiological bases of behavioral development in the first year
Herschkowitz N, Kagan J, Zilles K.
Neuropediatrics. 1997 Dec;28(6):296-306.

Neurobiological bases of behavioral development in the second year
Herschkowitz N, Kagan J, Zilles K.
Neuropediatrics. 1999 Oct;30(5):221-30.

Acquired reversible autistic syndrome in acute encephalopathic illness in children
DeLong GR, Bean SC, Brown FR 3rd.
Arch Neurol. 1981 Mar;38(3):191-4.

The onset of autism: patterns of symptom emergence in the first years of life
Ozonoff S, Heung K, Byrd R, Hansen R, Hertz-Picciotto I.
Autism Res. 2008 Dec;1(6):320-8.

A Prospective Study of the Emergence of Early Behavioral Signs of Autism
Sally Ozonoff et al.
J. Am. Acad. Child Adolesc. Psychiatry, 2010;49(3):258 268.
available here

Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children
Wakefield AJ et al.
Lancet. 1998 Feb 28;351(9103):637-41.
available here

Developmental regression and mitochondrial dysfunction in a child with autism
Poling JS, Frye RE, Shoffner J, Zimmerman AW.
Department of Neurology and Neurosurgery, Johns Hopkins Hospital
J Child Neurol. 2006 Feb;21(2):170-2.
{free online}

22. Hannah Poling, her medical issues, and her post-vaccinal regression into autism have been widely discussed. Her father and mother have participated in some of these discussions. Noteworthy is the fact that the U.S. Department of Health & Human Services conceded a suit regarding Hannah's vaccination-induce autism. Here are three examples regarding the significance of the HHS concession regarding Hannah Poling, mitochondria disorders, vaccinations, and autism:

Vaccine Injury Case Offers a Clue to the Causes of Autism
Could a group of disorders involving the "power plants of the cell" explain why some vaccinated children develop autism but the vast majority don't?
By Nikhil Swaminathan, April 22, 2008

Father: Child's case shifts autism debate
By Jon S. Poling
Atlanta Journal-Constitution, 04/11/08

Hanna Poling v. Secretary of HHS: Landmark First Concession of Vaccine-Induced Autism by U.S. Dept. of Health & Human Services

23. Generation Zero
{FOIA-based analysis of CDC's 1999 thimerosal findings}
Blaxill M, Safeminds 2004

A survey of vaccination studies fraught with conflicts of interest

Critiques of Danish studies regarding thimerosal and MMR

26. Neurodevelopmental Disorders after Thimerosal-Containing Vaccines: A Brief Communication
Geier MR, Geier DA.
Exp Biol Med 228:660664, 2003

27. Thimerosal exposure in infants and neurodevelopmental disorders: an assessment of computerized medical records in the Vaccine Safety Datalink.
Young HA, Geier DA, Geier MR.
J Neurol Sci. 2008 Aug 15;271(1-2):110-8. Epub 2008 May 15.

[These findings confirm the 1999 CDC findings of Verstraeten et al; see cite 23]

The study evaluated possible associations between neurodevelopmental disorders (NDs) and exposure to mercury (Hg) from Thimerosal-containing vaccines (TCVs) by examining the automated Vaccine Safety Datalink (VSD). A total of 278,624 subjects were identified in birth cohorts from 1990-1996 that had received their first oral polio vaccination by 3 months of age in the VSD. The birth cohort prevalence rate of medically diagnosed International Classification of Disease, 9th revision (ICD-9) specific NDs and control outcomes were calculated. Exposures to Hg from TCVs were calculated by birth cohort for specific exposure windows from birth-7 months and birth-13 months of age. Poisson regression analysis was used to model the association between the prevalence of outcomes and Hg doses from TCVs. Consistent significantly increased rate ratios were observed for autism, autism spectrum disorders, tics, attention deficit disorder, and emotional disturbances with Hg exposure from TCVs. By contrast, none of the control outcomes had significantly increased rate ratios with Hg exposure from TCVs. Routine childhood vaccination should be continued to help reduce the morbidity and mortality associated with infectious diseases, but efforts should be undertaken to remove Hg from vaccines. Additional studies should be conducted to further evaluate the relationship between Hg exposure and NDs.

28. Hepatitis B triple series vaccine and developmental disability in US children aged 1-9 years
 Gallagher C, Goodman M. Toxicol Environ Chem 2008 90(5):997-1008.
{free online}

29. Hepatitis B vaccination of male neonates and autism
[conference abstract as published]
CM Gallagher, MS Goodman, Graduate Program in Public
Health, Stony Brook University Medical Center, Stony Brook, NY
Annals of Epidemiology, p659
Vol. 19, No. 9 Abstracts (ACE) September 2009: 651680.

PURPOSE: Universal newborn immunization with hepatitis B vaccine was recommended in 1991; however, safety findings are mixed. The Vaccine Safety Datalink Workgroup reported no association between hepatitis B vaccination at birth and febrile episodes or neurological adverse events. Other studies found positive associations between hepatitis B vaccination and ear infection, pharyngitis, and chronic arthritis; as well as receipt of early intervention/special education services (EIS); in probability samples of
U.S. children. Children with autistic spectrum disorder (ASD) comprise a growing caseload for EIS. We evaluated the association between hepatitis B vaccination of male neonates and parental report of ASD.
METHODS: This cross-sectional study used U.S. probability samples obtained from National Health Interview Survey 19972002 datasets. Logistic regression modeling was used to estimate the effect of neonatal hepatitis B vaccination on ASDrisk amongboys age 317 years with shot records, adjusted for race, maternal education, and two-parent household.
RESULTS:Boyswho received the hepatitis B vaccine during the first month of life had 2.94 greater odds for ASD (nZ31 of 7,486; OR Z 2.94; p Z 0.03; 95% CI Z 1.10, 7.90) compared to later- or unvaccinated boys. Non-Hispanicwhite boys were 61% less likely to have ASD(ORZ0.39; pZ0.04; 95% CIZ0.16, 0.94) relative to non-white boys.
CONCLUSION: Findings suggest that U.S. male neonates vaccinated with hepatitis B vaccine had a 3-fold greater risk of ASD; risk was greatest for non-white boys.

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal
Waly M et al.
Mol Psychiatry. 2004 Apr;9(4):358-70.

Thimerosal induces DNA breaks, caspase-3 activation, membrane damage, and cell death in cultured human neurons and fibroblasts
Baskin DS, Ngo H, Didenko VV.
Toxicol Sci. 2003 Aug;74(2):361-8. Epub 2003 May 28.

Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism
James SJ et al. FASEB J. 2009 Aug;23(8):2374-83.

Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization
Westphal GA et al. Int Arch Occup Environ Health. 2000 Aug;73(6):384-8.

Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway
Makani S et al. Genes Immun. 2002 Aug;3(5):270-8.
{free online}

Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors
James SJ et al. Neurotoxicology. 2005 Jan;26(1):1-8.

Inhibition of the human erythrocytic glutathione-S-transferase T1 (GST T1) by thimerosal
Muller M et al. Int J Hyg Environ Health. 2001 Jul;203(5-6):479-81.

37. Pediatric MMR Vaccination Safety
Mark R. Geier, MD, PhD; David A Geier
International Pediatrics 2003;18(2):203-208.

The Vaccine Adverse Events Reporting System (VAERS) database was analyzed for the incidence rate of permanent brain damage, cerebellar ataxia, autism and mental retardation reported following MMR vaccine and diphtheria, tetanus and whole-cell pertussis (DTwcP) containing-vaccines from 1994 through 2000 in the US. Statistically significant increases in the incidence of serious neurologic disorders following pediatric MMR vaccine in comparison to DTwcP vaccine were found. The potentially globally destructive effects of natural measles, mumps and rubella infections means that continued vaccination is necessary, but improvements in MMR vaccines are needed to improve its safety.

38. A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism.
Geier DA, Geier MR.
Med Sci Monit. 2004 Mar;10(3):PI33-9. Epub 2004 Mar 1.

CONCLUSIONS: The results of this study agree with a number of previously published studies. These studies have shown that there is biological plausibility and epidemiological evidence showing a direct relationship between increasing doses of mercury from thimerosal-containing vaccines and neurodevelopmental disorders, and measles-containing vaccines and serious neurological disorders. It is recommended that thimerosal be removed from all vaccines, and additional research be undertaken to produce a MMR vaccine with an improved safety profile.

39. Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism
Singh VK, Lin SX, Yang VC.
Clin Immunol Immunopathol. 1998 Oct;89(1):105-8.

40. Acute Encephalopathy Followed by Permanent Brain Injury or Death Associated With Further Attenuated Measles Vaccines: A Review of Claims Submitted to the National Vaccine Injury Compensation Program
Received Jul 30, 1997; accepted Sep 23, 1997.
Robert E. Weibel*, Vito Caserta*, David E. Benor Dagger, and Geoffrey Evans*
>From the * Division of Vaccine Injury Compensation, National Vaccine Injury Compensation Program, Health Resources and Services Administration, Public Health Service, Rockville, Maryland; and the Dagger Office of the General Counsel, United States Department of Health and Human Services, Rockville, Maryland.
PEDIATRICS Vol. 101 No. 3 March 1998, pp. 383-387
{some highlights added in abstract}

Objective.  To determine if there is evidence for a causal relationship between acute encephalopathy followed by permanent brain injury or death associated with the administration of further attenuated measles vaccines (Attenuvax or Lirugen, Hoechst Marion Roussel, Kansas City, MO), mumps vaccine (Mumpsvax, Merck and Co, Inc, West Point, PA), or rubella vaccines (Meruvax or Meruvax II, Merck and Co, Inc, West Point, PA), combined measles and rubella vaccine (M-R-Vax or M-R-Vax II, Merck and Co, Inc, West Point, PA), or combined measles, mumps, and rubella vaccine (M-M-R or M-M-R II, Merck and Co, Inc, West Point, PA), the lead author reviewed claims submitted to the National Vaccine Injury Compensation Program...
Conclusions.  This clustering suggests that a causal relationship between measles vaccine and encephalopathy may exist as a rare complication of measles immunization.

41. [An excellent and thorough review]

Measles, mumps, rubella vaccine: through a glass, darkly.
Wakefield AJ, Montgomery SM.
Adverse Drug React Toxicol Rev. 2000 Dec;19(4):265-83; reviewer comments 284-92.

Lancet editor reverses himself: MMR and adverse events
Teresa Binstock, 2010

Vaccinations and autism: cause or coincidence?
Teresa Binstock, 2010

Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas
Palmer RF et al. Health Place. 2006 Jun;12(2):203-9.
{free online}

Proximity to point sources of environmental mercury release as a predictor of autism prevalence
Palmer RF et al. Health Place. 2009 Mar;15(1):18-24.
{free online}

46. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions
D'Amelio M et al.
Mol Psychiatry. 2005 Nov;10(11):1006-16.

47. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the san francisco bay area
Windham GC, Zhang L, Gunier R, Croen LA, Grether JK.
Environ Health Perspect. 2006 Sep;114(9):1438-44.
{free online}

OBJECTIVE: To explore possible associations between autism spectrum disorders (ASD) and environmental exposures, we linked the California autism surveillance system to estimated hazardous air pollutant (HAP) concentrations compiled by the U.S. Environmental Protection Agency. METHODS: Subjects included 284 children with ASD and 657 controls, born in 1994 in the San Francisco Bay area. We assigned exposure level by census tract of birth residence for 19 chemicals we identified as potential neurotoxicants, developmental toxicants, and/or endocrine disruptors from the 1996 HAPs database. Because concentrations of many of these were highly correlated, we combined the chemicals into mechanistic and structural groups, calculating summary index scores. We calculated ASD risk in the upper quartiles of these group scores or individual chemical concentrations compared with below the median, adjusting for demographic factors. RESULTS: The adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated solvents and heavy metals [95% confidence intervals (CIs) , 1.1-2.1], but not for aromatic solvents. Adjusting for these three groups simultaneously led to decreased risks for the solvents and increased risk for metals (AORs for metals: fourth quartile = 1.7 ; 95% CI, 1.0-3.0 ; third quartile = 1.95 ; 95% CI, 1.2-3.1) . The individual compounds that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene, and vinyl chloride. CONCLUSIONS: Our results suggest a potential association between autism and estimated metal concentrations, and possibly solvents, in ambient air around the birth residence, requiring confirmation and more refined exposure assessment in future studies.

Metabolic biomarkers of increased oxidative stress and impaired  methylation capacity in children with autism.
James SJ et al.  Am J Clin Nutr. 2004 Dec;80(6):1611-7

BACKGROUND: Autism is a complex neurodevelopmental disorder that  usually presents in early childhood and that is thought to be  influenced by genetic and environmental factors. Although abnormal  metabolism of methionine and homocysteine has been associated with  other neurologic diseases, these pathways have not been evaluated  in persons with autism. OBJECTIVE: The purpose of this study was to  evaluate plasma concentrations of metabolites in the methionine  transmethylation and transsulfuration pathways in children  diagnosed with autism. DESIGN: Plasma concentrations of methionine,  S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH),  adenosine, homocysteine, cystathionine, cysteine, and oxidized and  reduced glutathione were measured in 20 children with autism and in  33 control children. On the basis of the abnormal metabolic  profile, a targeted nutritional intervention trial with folinic  acid, betaine, and methylcobalamin was initiated in a subset of the  autistic children. RESULTS: Relative to the control children, the  children with autism had significantly lower baseline plasma  concentrations of methionine, SAM, homocysteine, cystathionine,  cysteine, and total glutathione and significantly higher  concentrations of SAH, adenosine, and oxidized glutathione. This  metabolic profile is consistent with impaired capacity for  methylation (significantly lower ratio of SAM to SAH) and increased  oxidative stress (significantly lower redox ratio of reduced  glutathione to oxidized glutathione) in children with autism. The  intervention trial was effective in normalizing the metabolic  imbalance in the autistic children. CONCLUSIONS: An increased  vulnerability to oxidative stress and a decreased capacity for  methylation may contribute to the development and clinical  manifestation of autism.

Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism.
James SJ et al.
Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):947-56.

Autism is a behaviorally defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-S-transferase (GST M1). We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.

Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism
James SJ et al.
Am J Clin Nutr. 2009 Jan;89(1):425-30. Epub 2008 Dec 3.

BACKGROUND: Metabolic abnormalities and targeted treatment trials have been reported for several neurobehavioral disorders but are relatively understudied in autism. OBJECTIVE: The objective of this study was to determine whether or not treatment with the metabolic precursors, methylcobalamin and folinic acid, would improve plasma concentrations of transmethylation/transsulfuration metabolites and glutathione redox status in autistic children. DESIGN: In an open-label trial, 40 autistic children were treated with 75 microg/kg methylcobalamin (2 times/wk) and 400 microg folinic acid (2 times/d) for 3 mo. Metabolites in the transmethylation/transsulfuration pathway were measured before and after treatment and compared with values measured in age-matched control children. RESULTS: The results indicated that pretreatment metabolite concentrations in autistic children were significantly different from values in the control children. The 3-mo intervention resulted in significant increases in cysteine, cysteinylglycine, and glutathione concentrations (P < 0.001). The oxidized disulfide form of glutathione was decreased and the glutathione redox ratio increased after treatment (P < 0.008). Although mean metabolite concentrations were improved significantly after intervention, they remained below those in unaffected control children. CONCLUSION: The significant improvements observed in transmethylation metabolites and glutathione redox status after treatment suggest that targeted nutritional intervention with methylcobalamin and folinic acid may be of clinical benefit in some children who have autism. This trial was registered at ( as NCT00692315.

The severity of autism is associated with toxic metal body burden and red blood cell glutathione levels
Adams JB et al.
J Toxicol. 2009;2009:532640. Epub 2009 Aug 26.

Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: part A--medical results
Adams JB et al.
BMC Clin Pharmacol. 2009 Oct 23;9:16.

Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: part B - behavioral results
Adams JB et al.
BMC Clin Pharmacol. 2009 Oct 23;9:17.

Porphyrinuria in childhood autistic disorder: implications for environmental toxicity
Nataf R, Skorupka C, Amet L, Lam A, Springbett A, Lathe R.
Toxicol Appl Pharmacol. 2006 Jul 15;214(2):99-108.

An investigation of porphyrinuria in Australian children with autism
Austin DW, Shandley K.
J Toxicol Environ Health A. 2008;71(20):1349-51.

Evidence of Mitochondrial Dysfunction in Autism and Implications for Treatment
Daniel A. Rossignol, J. Jeffrey Bradstreet
American Journal of Biochemistry and Biotechnology 4 (2): 208-217, 2008
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