Autism and Autism Spectrum Disorders and the Connection to Exposures to Perfluoroalkyl Chemicals
I think it is now well established that the rate of autism has been going up around the globe over at least the last 20 years (although there has been recent doubt cast on this because of a study done in England. Near the end of this write up, I discuss briefly why I think that the study is flawed.) I believe that there will soon be an overwhelming consensus that the cause of this increase is the result of a combination of genetic susceptibility and an environmental trigger or triggers. There are many possible environmental culprits from which to choose. Between 1,000 and 3,000 new chemicals come into use every year with virtually no toxicity testing requirements. Also, the industrial world and much of the developing world are seeing the rapid expansion of the use of electromagnetic signaling devices. Although there are many nasty neuro-developmental toxins in the environment, not many fit a few very basic requirements that would be needed in order to explain the rise in autism in so many diverse parts of the globe and in so many different cultural settings. Whatever the environmental trigger or triggers are, they have to meet at least these five criteria:
Given this list of restrictions there are significantly fewer candidates for the trigger mechanism/mechanisms. The five most likely candidates as possible triggers appear to be:
· Chemicals associated with plastics,
· Chemicals associated with fire retardants,
· Perfluoroalkyl chemicals (PFCs),
· Silicone based chemicals, and
· Electromagnetic signaling (EM).
There are likely other candidates, but the research I completed to date does not indicate other candidates that could fit the profile. Chlorinated solvents, pesticides, PCB, PBBs, DDT, dioxins, heavy metals (such as lead and mercury) have all previously been identified as problem chemicals and huge efforts have been made to reduce exposures to them. The levels of these chemicals in our blood have generally been declining at roughly the same time that the autism rate has been rising, so none of them seem to be good candidates as ubiquitous triggers. Many other chemicals have not been around long enough or widely used enough, when compared to the five possible triggers mentioned above, to have caused such a widespread problem.
I have not done sufficient research on each of the five most likely factors listed above to definitively exclude any of them, but I do have reasons to suspect that the rate of manufacture and use of PFCs present the best match to the autism data and information available (based upon distribution, exposure, and autism cluster/distribution patterns). What I want to present is a weight of evidence explanation to support this association. Any one fact can easily be discounted in any number of ways. Some of what will be presented will come from well thought out, well researched studies. Other information will be very weak -- (for example, the autism rate in China has been reported to be increasing 20% per year. It is impossible to determine how this was calculated because China does not keep good records on the incidence of autism. However, there are other lines of evidence that indicate that the Chinese are becoming alarmed by the rise of autism in their country and that has implications for the discussion on PFCs as a possible trigger of autism.) Thus, the reader is advised to sift through the arguments and the literature for themselves.
The final disclaimer is that I am not a toxicologist, epidemiologist, medical doctor, or even a biologist. I fall into the generalist category when it comes to science (other than my familiarity with contaminant fate and transport in the environment). I don’t pretend to fully understand every article I cite. Again, it is a weight of evidence approach that I am taking and being a generalist is actually an advantage for such an approach.
PFCs come in many forms. The most easily recognized forms are Teflon® and ScotchGuard®, but it needs to be realized that these are just two out of thousands of consumer products that contain or have contained PFCs. I have only supplied the names of these two products to give the reader some context for what these compounds are. Also, there are at least 400 compounds that are classified as PFCs and there are literally thousands of manufacturers who either produce PFCs or use them in their products. In the literature however, the PFCs that are most commonly referred to are perfluorooctane sulfonate (PFOS) and perfluoroctanoic acid (PFOA). Most of the toxicological and epidemiological studies have been performed on these two contaminants as they are found the most frequently in the environment and in human blood serum. Also, many of the other PFCs eventually break down to form either PFOS or PFOA in nature and in humans. These PFOS/PFOA subunits generally will not break down further. A most important distinction between PFCs and other contaminants is that they tend to partition primarily to proteins rather than to fats or water. As proteins make up so much of the important systems of our cells and biochemistry, PFCs have the potential to negatively impact numerous processes in our bodies.
With minimal research on the internet, PFCs can be shown to match Items 1, 2, 4, and 5 above. They are found around the globe in human populations. They were invented in the 1940s and the uses of PFCs have steadily grown. They were thought to be biologically inactive and they pass the placental barrier. Meeting the criteria of Item 3 however is what, to a great extent, separates PFCs as a possible trigger mechanism from the other possible triggers mentioned above.
As was stated, PFCs were thought to be biologically inactive until around the 2000 when field studies began to show global contamination by PFCs and laboratory studies began to demonstrate significant toxicity in laboratory animals. The first question that must be asked about PFCs is whether they could be developmental neurotoxins. There are multiple studies that show the potential for PFCs to disrupt human neurodevelopment. The following are some examples:
· In vitro exposure to developing brain cells caused misdirected cell creation (the wrong cells developed when dividing brain cells were exposed to PFOS).10
· Laboratory mice and rats contaminated with PFCs experienced brain damage when exposed to ultra-sound.15, 16
· PFCs impact gene expression and proteins which may impact neurologic development.23, 25
This is not an effort to demonstrate that PFCs are a potent human neurotoxin at environmentally relevant concentrations. It is only to point out that PFCs do have the potential to impact neurodevelopment in humans. A great deal of research still needs to be done on the toxicity of PFCs. Polybrominated diethyl ethers (PBDEs - fire retardants) also show possible human neurotoxic effects and are fairly ubiquitous. That is why both families of chemicals are good suspects as trigger mechanisms. However, the possibility of being a human developmental neurotoxin is only one more piece of data in a weight of evidence analysis. As yet, I am not aware of any evidence of silicon based chemicals possibly being developmental neurotoxins, but that does not rule them out. Whatever the triggers of autism are, they have not previously been suspected of being highly toxic. Thus, PFCs, PBDEs, plasticizers, silicone-based chemicals, EM signals, or other possible causes must also be evaluated for neurotoxicity.
What follows is the “evidence” to consider when looking at PFCs as the possible trigger mechanism.
A) Autism is more prevalent among the wealthy and well educated in the United States57. PFC serum levels have been shown to be higher in Caucasians, the wealthy, and more educated1, 29, 44, 45, 46, 47. Caucasians are wealthier on average in America than their fellow citizens of African-American or Hispanic descent. The wealthier people are and the more educated they are, the more likely they are to eat more seafood (food sources with higher PFC contamination), buy new cars, buy high performance outerwear, buy electronics and computers, replace electronics and computers, replace carpets, replace treated flooring, repaint home interiors, replace treated furniture, and eat out more frequently. All of these behaviors expose the participants to higher levels of PFCs. Thus PFC exposure is higher in the wealthier Americans and more educated Americans and that coincides with higher rates of autism.
B) Autism rates are higher along expressways11. The main source of “non-point source” contamination of waterways by PFCs in Japan was found to be major transportation corridors12. PFCs are used in automotive lubricants, tires, wax, gaskets, hoses, windshield wiper fluids, fabrics, etc. PFCs are being released in substantial quantities from the transportation system. Thus, those who are the most exposed to transportation related pollution are also more likely exposed to higher levels of airborne PFCs.
C) Autism rates are higher among the offspring of the US military13. The US military uses large quantities of PFC-based fire suppressants and does extensive training with those fire suppressants. They are also early adopters of technology (e.g., electronics and computers), they have an emphasis on cleanliness, and they use high performance outerwear a great deal. They update their facilities, drive newer vehicles, and replace those vehicles frequently. Their equipment uses PFC-containing lubricants and hydraulic fuels. This has resulted in higher than average PFC exposure to the military personnel and their families and widespread PFC contamination of groundwater and surface water at military bases (personal experience).
D) Autism rates are higher in the children of people who shampoo their pets for fleas14. PFCs are used in shampoos and in pesticides. There is a pesticide that is usually associated with flea shampoos that is not a PFC. However, it partitions to the fats unlike PFCs. PFCs make excellent wetting solutions and getting pet shampoo to penetrate thick fur would likely lead to preferential the use of PFC containing products. PFCs as a surfactant are also reported to be gentle on skin as well.
E) Autism rates are among the highest in the nation in states with known widespread PFC contamination47, 48, 52. Minnesota and New Jersey which have documented high level PFC contamination in groundwater and drinking water, report some of the highest autism rates in the nation, with Minnesota often listed as the state with the highest autism rate in the nation. Minnesota is the home of 3M, the inventors many PFC formulations and was one of the major manufacturers of PFCs in the world.
Autism rates reported by various states are impacted by how statistics are kept, by how autism is reported, state awareness of the problem, etc. There is very little data on how extensive PFC contamination is in most states, so it is difficult to assess the relationship between the individual states’ autism rates and PFC contamination levels in people in those various states. Still, it is striking that Minnesota, the home of 3M and a state that has documented a high level of contamination in its waters and fish population would also be one of the leaders, if not the leader, in the occurrence of autism in the US.
F) In laboratory tests of rats and mice fed PFCs, brain damaged occurred when the contaminated mice and rats were exposed to ultrasound15, 16. Ultrasound has possibly been linked to autism17, 49.
G) Autism occurs approximately 5 times more frequently in males than in females18, 19, 43. PFC impacts are influenced by estrogen and testosterone levels and PFCs have measurable but variable effects between males and females in animals and humans20, 21, 50, 51.
H) Autism results from variable gene expressions over numerous genes22. PFCs affect how numerous genes are expressed23, 25, 26.
I) Autism is chiefly indicated by social inabilities. The best predictor of autism is a deficit in reciprocal social interactions27. PFC contamination during in utero development was associated with reduced prosocial behavior in 7 year olds28.
J) Caucasians in the US have higher rates of autism than non-Caucasians53. Caucasians in the US have higher levels of PFCs in their blood serum that non-Caucasians29.
K) Autism rates are higher in those who seek fertility treatment24. PFCs reduce fertility and those couples having troubles conceiving are more likely to seek fertility treatments31.
L) Autism is associated with mitochondrial damage54, 55. PFCs damage mitochondria32, 33. Additionally, PFCs interfere with gene expression which may affect fetal development if the original mitochondrial containing cells are contaminated.
M) Autism rates are higher for those who are born underweight and/or early36. PFCs cause low weight babies34, 35.
N) Higher autism rates are linked to postpartum thyroid problems37. PFCs are implicated in some thyroid disease38.
O) Higher autism rates are linked to wetter climates43. In wetter climates people spend more time indoors where PFC levels in air are typically higher than in ambient outdoor air. In wetter climates people use high performance outerwear more frequently than in drier climates. Rain/precipitation removes PFCs from the air and deposits them in soils, groundwater, and surface water39. All of these factors would likely lead to higher rates of PFC exposure in wetter climates.
P) The autism rate is much lower among the Amish40. The Amish grow much of their own food. They do not heavily use mechanized transportation. They do not eat in fast food restaurants as frequently. They make their own clothes. They do not have modern electronics and computers in their homes. They are generally in less contact with PFC containing products and environments.
Q) In China the rate of autism is increasing more quickly than in the United States and Europe43. The Chinese took over manufacture of PFCs as US and European countries stopped making many of these chemicals56. It is also reported that Chinese women have approximately 3 times as much PFC in their blood serum as US Women. The rate of autism in China is not well documented. They do not keep good statistics on autism. They tend to “hide” their autistic children and there is no governmental help for families with autistic children. However, there is increasing evidence that the Chinese are becoming aware of this rising problem in their population.
R) Autism is thought to be a brain connectivity problem9. In vitro studies modeling PFCs impact on developing human brain cells suggest that PFCs caused improper cell differentiation (potentially leading to “brain miswiring. 10”)
S) Autism is associated with immune system dysfunction in both child and mother6, 8, 43. PFCs (especially PFOS) interfere with immune system expression2, 3, 4, 7. PFOS provokes an inflammation like response in fetal rat brains7. Of particular interest are the indications that auto-antibodies to fetal neuro-proteins are passing from human mothers into the plasma of their fetuses in a significant percentage of children who eventually turn out to be autistic. The same is not true for children who never develop autism. I am not familiar with immune system science, but it would seem odd that the mother’s immune system would attack proteins in the developing fetal brain, unless something about those proteins were abnormal or foreign. As PFCs bind to proteins, in some instances might the protein appear to be abnormal to the mother’s immune system?
As stated above I am not trying to “prove” that PFCs are triggering autism, but suggest that the relationship between PFCs and autism should be explored. The evidence to me is highly suggestive that PFCs are at least a prime suspect.
There has been some recent questioning of whether the “autism epidemic” is real. I have become convinced that it is real. The question has been reinforced because of a recent British study comparing the rate of autism in Britons over 16 to those of younger children. The difficulty with such a study is that if something like PFCs is the trigger mechanism, exposure rates are changing in various countries. For instance, since 3M discontinued making PFOS, levels of PFOS have decreased in American blood serum. However, levels of other PFCs have begun to increase in American blood serum as these other PFCs are substituted for the discontinued use of PFOS/PFOA in products. The European Union has banned most uses of long chain PFCs. It stands to reason that PFC contamination of the European population will begin to change. If indeed PFCs are triggering autism, then longitudinal studies of autism rates are going to show uneven changes in those rates between different countries. The same can be said of the other possible triggers. One needs to look at the pattern of use and exposure and then watch the autism rates to determine if there is a cause and effect.
There are numerous ways of testing the hypothesis of PFCs as the trigger mechanism. It will be interesting to see if autism rates start to go down in Europe, slow in the US, and continue to accelerate in China. One epidemiological study that would definitely help our understanding of the cause and effect relationship is to look at autism rates of children of young women who work in different professions. PFC exposures for young women in the textile/carpet making industries for instance, would likely be much higher than for say young women working as bakers. Additionally, epidemiological studies done on Department of Defense (DoD) personnel could be fruitful. DoD keeps excellent records of their personnel. They have a first class medical system and they are alerted to the problem of autism in their offspring. Numerous DoD sites will likely have had, or still have, water systems impacted by PFCs due to the extensive uses of firefighting foams and other materials containing PFCs around these facilities. Correlating birth outcomes/autism rates for children born at facilities where the residential water supply was impacted with PFCs (especially PFOS), compared to birth outcomes from non-impacted DoD sites might shed light on the possibilities of PFCs being a major trigger of autism.
I have a great deal more literature on PFC distribution, PFC toxicology and the biology of autism. This has not been an exhaustive discussion of the possible link between PFCs and autism. But I am not seeing much, if any, discussion on the internet of the possible link, so I want to see it scrutinized and evaluated more openly, at least among the research community.
For additional information, please go to:
1. Perforce, Perfluorinated Organic Compounds in the European Environment, Scientific Report, Project Coordinator, Dr. Pim de Voogt 2004, (page 66), Institute for Biodiversity and Ecosystem Dynamics (Draft)
2. GESTATIONAL EXPOSURE TO PERFLUOROOCTANE SULFONATE (PFOS) SUPPRESSES IMMUNE FUNCTION IN B6C3F1 MICE, Deborah E. Keil, Tracey Mehlmann, Leon Butterworth† and Margie M. Peden-Adams, National Institute for Occupational Safety and Health, Morgantown, WV, USA, Clinical Laboratory Sciences, University of Nevada, Las Vegas, NV USA, Department of Pediatrics and the Marine Biomedicine and Environmental Science Center, Medical University of South, Carolina, Charleston, SC, USA Page 1 of 40 Toxicological Sciences, ToxSci Advance Access published February 5, 2008
3. Effects of environmentally-relevant levels of perfluorooctane sulfonate on clinical parameters and immunological functions in B6C3F1 mice, January-March 2011, Vol. 8, No. 1 , Pages 17-29 (doi:10.3109/1547691X.2010.527868), Patricia A. Fair, Erin Driscoll, Meagan A. M. Mollenhauer, Sarah G. Bradshaw, Se Hun Yun, Kurunthachalam Kannan, Gregory D. Bossart, Deborah E. Keil, Margie M. Peden-Adams, Journal of Immunotoxicology
4. Immunotoxicity of Perfluorooctanoic Acid and Perfluorooctane Sulfonate and the Role of Peroxisome Proliferator-Activated Receptor Alpha, January 2009, Vol. 39, No. 1 , Pages 76-94, Critical Reviews in Toxicology, Jamie C. DeWitt, Alexander Shnyra, Mostafa Z. Badr, Scott E. Loveless, Denise Hoban, Steven R. Frame, Robyn Cunard, Stacey E. Anderson, B. Jean Meade, Margie M. Peden-Adams, Robert W. Luebke, Michael I. Luster
5. Prenatal immune challenge is an environmental risk factor for brain and behavior change relevant to schizophrenia: evidence from MRI in a mouse model. Li Q, Cheung C, Wei R, Hui ES, Feldon J, Meyer U, Chung S, Chua SE, Sham PC, Wu EX, McAlonan GM., Department of Psychiatry, University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China. PLoS One. 2009 Jul 24;4(7):e6354. PubMed
6. DETECTION OF AUTOANTIBODIES TO NEURAL CELLS OF THE CEREBELLUM IN THE PLASMA OF SUBJECTS WITH AUTISM SPECTRUM DISORDERS, Brain Behav Immun. 2009 January; 23(1): 64â€“74. Published online 2008 July 30. doi: 10.1016/j.bbi.2008.07.007. Sharifia Wills, Maricel Cabanlit, Jeff Bennett, Paul Ashwood, David G. Amaral, and Judy Van de Water, PubMed
7. Inflammation-like glial response in rat brain induced by prenatal PFOS exposure, Huai-cai Zeng, Ling Zhang, Yuan-yuan Li, Yan-jian Wang, Wei Xia, Yi Lin, Jie Wei and Shun-qing Xu, NeuroToxicology, Volume 32, Issue 1, January 2011, Pages 130-139
8. Section of report entitled: Infection and Immune Dysfunction in The Epidemiology of Autism Spectrum Disorders*Annual Review of Public Health, Vol. 28: 235-258 (Volume publication date April 2007), First published online as a Review in Advance on January 2, 2007, DOI: 10.1146/annurev.publhealth.28.021406.144007, Craig J. Newschaffer, Lisa A. Croen, Julie Daniels, Ellen Giarelli, Judith K. Grether, Susan E. Levy, David S. Mandell, Lisa A. Miller, Jennifer Pinto-Martin, Judy Reaven, Ann M. Reynolds, Catherine E. Rice, Diana Schendel, and Gayle C. Windham
9. Annual Meeting Mini-Symposium, Autism and Abnormal Development of Brain Connectivity, Matthew K. Belmonte,1 Greg Allen,2 Andrea Beckel-Mitchener,3 Lisa M. Boulanger,4 Ruth A. Carper,5 and Sara J. Webb6, 9228 • The Journal of Neuroscience, October 20, 2004 • 24(42):9228 –9231
10. Developmental Neurotoxicity of Perfluorinated Chemicals Modeled in Vitro, Theodore A. Slotkin,1 Emiko A. MacKillop,1 Ronald L. Melnick,2 Kristina A. Thayer,2 and Frederic J. Seidler1, 716 VOLUME 116 | NUMBER 6 | June 2008 • Environmental Health Perspectives
11. Volk, H.E. Environmental Health Perspectives, published online Dec. 16, 2010., From WebMD Health News, Fast Lane to Autism: Living Near Freeways,Daniel J. DeNoon
12. TRAIN STATION AS AN INDICATOR OF THE NONPOINT SOURCE OF PERFLUORINATED COMPOUNDS IN URBAN RIVER BASIN, Zushi Yasuyuki and Masunaga Shigeki, Graduate School of Environment and Information Sciences, Yokohama National University, 79-7 Tokiwadai, Hodogaya, Yokohama, Kanagawa 240-8501, Japan
13. Area resources help counter high autism rate at Fort Leavenworth, Apr 9, 2010, By Melissa Bower, Fort Leavenworth Lamp, http://www.army.mil/
14. Household Pesticide Use in Relation to Autism, Irva Hertz-Picciotto, MPH, PhD, Public Health Sciences and the M.I.N.D. Institute, University of California at Davis, Dept PHS, Davis, CA 95616, Isaac N. Pessah, PhD, 3 Department of Veterinary Molecular Biosciences, University of California at Davis, M.I.N.D. Institute, One Shields Avenue, Davis, CA 95616, Robin Hansen, Pediatrics and the M.I.N.D. Institute, University of California at Davis, 2825, 50th Street, Sacramento, CA 95817, and Paula Krakowiak, MS, M.I.N.D. Institute, University of California at Davis, 2825 50th Street, Sacramento, CA 95817.
15. Neurotoxicity of perfluoroctane sulfonate (PFOS) in rats and mice after a single oral exposure, Itaru Sato, Kosuke Kawamoto, Yasuo Nishikawa, Shuji Tsuda, Midori Yoshida, Kaori Yaegashi, Norimitsu Saitl, Wei Liu and Yihe Jin, The Journal of Toxicological Sciences (J.Toxicol, Sci.), Vol 34, No.5, 569-574, 2009
16. Ultrasonic-induced tonic convulsion in rats after subchronic exposure to perfluoroctance sulfonate (PFOS), Itaru Sato, Kosuke Kawamoto, Shuji Tsuda, Midori Yoshida, Kaori Yaegashi, Norimitsu Saitl, Wei Liu and Yihe Jin, The Journal of Toxicological Sciences (J.Toxicol, Sci.), Vos 36, No. 1, 55-62. 2011
17: Potential teratogenic effects of ultrasound on corticogenesis: Implications for autism, E.L. Williams, M.F. Casanova, Medical Hypotheses - July 2010 (Vol. 75, Issue 1, Pages 53-58, DOI: 10.1016/j.mehy.2010.01.027)
18. Rare De Novo Variants Associated with Autism Implicate a Large Functional Network of Genes Involved in Formation and Function of Synapses, Volume 70, Issue 5, 9 June 2011, Pages 898-907, Sarah R. Gilman, Ivan Iossifov, Dan Levy, Michael Ronemus, Michael Wigler and Dennis Vitkup, http://dx.doi.org/10.1016/j.neuron.2011.05.021
19. Sarachana T, Xu M, Wu R-C, Hu VW (2011) Sex Hormones in Autism: Androgens and Estrogens Differentially and Reciprocally Regulate RORA, a Novel Candidate Gene for Autism. PLoS ONE 6(2): e17116. doi:10.1371/journal.pone.0017116, February 16, 2011
20. Oxford Journals, Life Sciences, Medicine, Toxicological Sciences Volume120, Issue1, Pp. 42-58. Estrogen-Like Activity of Perfluoroalkyl Acids In Vivo and Interaction with Human and Rainbow Trout Estrogen Receptors In Vitro,Abby D. Benninghoff, William H. Bisson, Daniel C. Koch, David J. Ehresman, Siva K. Kolluri and David E. Williams
21. Journal of Environmental and Public Health, Volume 2009 (2009), Article ID 268219, 10 pages, doi:10.1155/2009/268219,Dietary Predictors and Plasma Concentrations of Perfluorinated Compounds in a Coastal Population from Northern Norway, Charlotta Rylander, Magritt Brustad, Helena Falk, and Torkjel M. Sandanger
22. Rare De Novo Variants Associated with Autism Implicate a Large Functional Network of Genes Involved in Formation and Function of Synapses, Volume 70, Issue 5, 9 June 2011, Pages 898-907, Sarah R. Gilman, Ivan Iossifov, Dan Levy, Michael Ronemus, Michael Wigler and Dennis Vitkup, http://dx.doi.org/10.1016/j.neuron.2011.05.021
23. Neonatal Exposure to PFOS and PFOA in Mice Results in Changes in Proteins which are Important for Neuronal Growth and Synaptogenesis in the Developing Brain, Niclas Johansson, Per Eriksson and Henrik Viberg1, Department of Environmental Toxicology, Uppsala University, Uppsala, Sweden, Toxicol. Sci. (2009) 108 (2): 412-418. doi: 10.1093/toxsci/kfp029 First published online: February 11, 2009
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26. Transcriptional Effects of Prenatal and Neonatal Exposure to PFOS in Developing Rat Brain,Faqi Wang, Wei Liu, Yihe Jin, Jiayin Dai, Wenguang Yu, Xiaohui Liu and Li Liu, School of Environmental and Biological Science and Technology, Dalian University of Technology, Key Laboratory of Industrial Ecology and Environmental Engineering, MOE, Dalian 116024, China, Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China, and Division of Hygienic Toxicology, School of Public Health, China Medical University, North 2 Road 92, Shenyang, Liaoning 110001, China,Environ. Sci. Technol., 2010, 44 (5), pp 1847–1853, DOI: 10.1021/es902799f, Publication Date (Web): February 5, 2010, Copyright © 2010 American Chemical Society
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28. Prenatal Exposure to Perfluorinated Chemicals and Behavioral or Coordination Problems at Age 7, Chunyuan Fei and Jørn Olsen, doi: 10.1289/ehp.1002026 (available at http://dx.doi.org/), Online 9 November 2010, ENVIRONMENTAL HEALTH PERSPECTIVE, Page 13
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