Recent research has demonstrated that low level exposure to organophosphate pesticides in pregnant women can have significant and lasting effects upon childhood cognitive development. Significant changes in IQ have been noted as well as increases in pervasive developmental disorder, a decline in mental development, poor attention skills, and hyperactive behavior.1,23 This can be of great concern because of the prevalence of these chemicals in the environment and the ease with which one can be exposed and never be aware of it. Fortunately, exposure to these compounds can be easily screened for by using a simple urine test, and methods of avoidance and detoxification can be implemented.
The three common classes of nonpersistent pesticides in use today include organophosphates, carbamates, and pyrethroids. Approximately 40 organophosphate pesticides are registered with the EPA, and some 60 million pounds are applied to approximately 60 million acres of US agricultural crops every year, plus an additional 17 million pounds are used in other areas.1-3 Organophosphates include chemical mixtures to control insects (insecticides), weeds (herbicides), fungi (fungicides), or other pests (e.g., rodenticides).4 These chemicals account for a large share of all insecticides used in the US. Research has noted that diet is the primary route of exposure.1 Organophosphates work primarily by acting as a neurotoxin, inhibiting acetylcholinesterase in the central and peripheral nervous system, leading to excess acetylcholine and a range of neurologic symptoms.1,2 The most commonly known organophosphate is adenosine triphosphate (ATP). ATP functions in all living things to convert chemical energy into biological functions and is made up of adenosine as the "organo" group that is linked to phosphate (PO4−). Any compound that mimics the structure of ATP has the potential to disrupt multiple biological functions. In the breakdown process, about 75% of organophosphates are converted to breakdown products called dialkyl phosphate metabolites (Table 1). Assessment of these metabolites indicates a person's level of exposure. These metabolites themselves may also account for some of the effects of organophosphates seen at lowered, chronic doses.5
Table 1: Reference Ranges Are Found in the Fourth Report on Human Exposure to Environmental Chemicals by the CDC, for Most Recently Available Survey Years 2003-2004
Two chemical changes occur in the body that lead to the production of organophosphate metabolites measured in urine. The first chemical change is the conversion of sulfur to oxygen, producing a more potent acetyl cholinesterase inhibitor. The second is the hydrolysis of the organophosphate, which yields a metabolite. Hydrolysis of the organophosphates decreases the toxicity, as the metabolites do not inhibit acetyl cholinesterase. Hydrolysis cannot occur without the enzyme paraoxonase (PON1), making individuals homozygous for PON1Q192 more susceptible to organophosphate toxicity.6-8 This relatively common single nucleotide polymorphism (SNP) can significantly enhance the damage that organophosphate pesticides can cause in utero.
Exposures May Also Cause Infertility
Farm workers, gardeners, pesticide applicators, and manufacturers of organophosphates have greater exposure than the general population and provide most of the early data on exposure.2 Though organophosphates are widely used in agricultural products brought into the home, as well as available for home use, questions have been raised about whether exposure to levels currently regarded as safe could result in clinical manifestations, such as an adverse impact on fertility, infant growth, and childhood development.4 Increasing the difficulty of association is that chronic exposure can lead to significant though vague and multiple symptoms including fatigue, weakness, irritability, depression, and forgetfulness, which may cause difficulty in establishing a diagnosis.2,9 Animal studies have provided substantial toxicological evidence that repeated low-level exposure to organophosphate pesticides may affect neurodevelopment and growth in developing animals.10 There are also reports of organophosphate exposure in men and women working on or living near farms worldwide and adverse reproductive outcomes, as well as associations between pesticide exposures representative of the general population and reduced semen quality.11,12 In 2005, the Stanford University School of Medicine and the Collaborative on Health and the Environment brought together 40 experts in infertility and reproductive health who noted that there were significant concerns regarding the effects of organophosphate on fertility. In 2002 the US National Center for Health Statistics reported that about 7.3 million women said that they had experienced impaired fecundity, an increase from the 6.1 million women in 1995, and 4.9 million in 1988 who had reported an increase.13,14 The National Survey of Family Growth also suggested the possibility that biological fertility challenges themselves may be on the rise, since younger women appear to experience more issues than women who are older. Only 6% of women 35 and older reported an issue with infertility between 1982 and 1995, while 42% of women under age 25 reported difficulty in becoming pregnant. Additionally, some research has noted that certain conditions linked to infertility appear to be increasing, ranging from testicular cancer and poor semen quality to endometriosis.15
Lasting Metabolic Disruption in Children
Certainly, the biggest concern is that early-life organophosphate exposures may lead to lasting metabolic disruption in children.1In newborns, the effects of organophosphate exposure are mainly exhibited as an increased number of abnormal reflexes, while in adolescents, the effects manifest as mental and emotional problems.16,17 Organophosphates are known to cross transplacentally to the child. There are documented reports of neonates being born to mothers who had consumed excessive amounts of organophosphorus compounds before delivery, resulting in infants with signs and symptoms of organophosphorus poisoning.18 Based on occupation and lifestyle questionnaires, several studies have correlated possible in utero exposures to negative health outcomes. In a large study of the medical birth registry in Norway, 192,417 children born between 1967 and 1991 to parents identified as farmers had a moderately increased risk for spina bifida and hydrocephaly, and limb reduction defects were associated with pesticide exposure.19 In a prospective case control study of 465 infants born in a hospital over a two-year period in Latin America, a correlation between the incidence of congenital malformations and the parent's exposure to pesticides was also noted. The study only included live births, though there were 18 stillborn infants.20 Another study of South African women farmers and children noted a link between exposure to pesticides and certain birth defects.21 In a study of mothers and children from Northern Ecuador exposed to pesticides, direct assessment of erythrocyte acetylcholine esterase activity and urinary excretion of organophosphate metabolites found that increased excretion of diethyl metabolites were associated with slowed reaction times in children. The authors propose that prenatal pesticide exposure may cause lasting neurotoxic damage as well as exacerbate the effects of malnutrition in developing countries.22
The CHAMACOS study is a longitudinal birth cohort study of the effects of pesticides such as organophosphates in 526 live single births, delivered by women residing in an agricultural community in California. The study found that prenatal organophosphate exposure was associated with increases in pervasive developmental disorder, a decline in mental development, poor attention skills, and hyperactive behavior. It also found that prenatal exposure to organophosphates, as noted by urine metabolites during the first and second half of pregnancy, were associated with lower cognitive scores for the children at 7 years of age. The association was most pronounced when comparing children in the highest to lowest quintiles of prenatal exposure, experiencing a full 7-point decrease in IQ scores for those children whose mothers had the highest urinary organophosphate metabolite levels.23
In another study of over 1000 children (8-15 years old), those with higher levels of organophosphates from common household exposures were found to be significantly more likely to be diagnosed with attention deficit/hyperactivity disorder.1 The data, collected from the July 2005 National Report on Human Exposure to Environmental Chemicals by the US Centers for Disease Control (CDC), report exposure data for 148 chemicals and their breakdown products in a representative cross-section of Americans who participated in the National Health and Nutrition Examination Survey (NHANES). More than 93% of children had at least 1 detectable metabolite of the 6 organophosphates measured. Levels were higher in the 2003-2004 survey than the 2000 survey.24 Children's primary exposure is from diet. The study found that a 10-fold increase of DMAP metabolites (dimethylthiophosphate [DMTP] and dimethyldithiophosphate [DMDTP]), which corresponded to going from the 25th percentile to the 75th percentile in level of exposure, had a 55% to 72% increase in the odds of being diagnosed with ADHD.1 These findings are significant because NHANES is a nationally representative sample of the US population. These are not findings of high-risk children living in agricultural communities. In these studies, the children's own organophosphates levels were not linked to their IQs, suggesting that prenatal exposure alone is largely responsible for the decline in IQ. The correlation of organophosphate exposure and ADHD rates are similar to the data 30 to 40 years ago in relation to lead exposure and IQ, and as has been discovered with lead, even small exposures can be harmful.25
Treatment for Acute or Chronic Effects
Treatment for acute or chronic effects of these toxins includes avoidance and detoxification support. Avoidance for individuals using organophosphates includes wearing protective clothing, removing and washing clothes upon entering home, and cleansing skin with warm water and soap. Nutrition can also have an impact. In a comparison of children who regularly consumed organic foods versus conventional, consumption of organic foods was found to reduce children's exposure from above to below the EPA's current guidelines. The median total dimethyl metabolite concentration was approximately six times higher for children with conventional diets than for children with organic diets.26 Ensuring adequate docosahexanoic acid (DHA) may also help to increase antioxidant activity in the brain and prevent organophosphates induced damage.27 Antioxidants nutrients, including vitamin E, vitamin C, and alpha-lipoic acid, may also protect against organophosphate-induced oxidative stress.27,28 Supplementation with nutrients to stimulate detoxification (especially taurine, glycine, and N-acetylcysteine) may be useful in reducing body burden of organophosphates.
Public health programs and government regulations have made great strides in reducing the effects of lead on children.29 PCB production was also banned in North America over 30 years ago due to health concerns. It would be difficult for one to argue against these rules and laws that protect unborn and young children from permanent or persistent damage. The removal of lead from paint and gasoline, and PCB use in industry was based on less evidence than has now accrued for organophosphates.10,30 There would be a great public outcry if a store sold toys with lead paint, yet no alarms are sounded when an exterminator comes to a house where a pregnant woman and/or child lives.
Elizabeth Redmond, PhD, MMSc, completed her master of medical science and RD degrees at Emory University in Atlanta, and her doctorate in nutrition from the University of Georgia. Though she has worked, written, and spoken on various nutrition topics, her current interests include evaluating the effects of inflammation on gastrointestinal disorders, vitamin D and its relationship to inflammatory markers, and assessment of vitamin status. Dr. Redmond has appeared on CNN, on the CWK Network, and as a speaker at many functional- and integrative-medicine related conferences. Her work has been published in peer reviewed journals, and she is coauthor of Laboratory Evaluations for Integrative and Functional Medicine (2008). Dr. Redmond is currently working at the Metametrix Institute, a division of Metametrix Clinical Laboratory.
Christie Egeston, MS, received her master of science degree in medical sciences from Hampton University. Ms. Egeston has worked in several capacities within the medical field, including as a laboratory assistant at Vanderbilt University Medical Center. She joined Metametrix in 2005 as a client services support specialist and was later promoted to education specialist. In the former role, Ms. Egeston helped to prepare materials for Hawthorne Institute seminars and compiled research in support of supplement recommendations used in Metametrix testing.
J. Alexander Bralley, PhD, Metametrix chief executive officer, received his doctorate in medical sciences from the University of Florida College of Medicine in 1980. As founder of Metametrix (1984), he has been instrumental in developing nutritional/metabolic analyses and application guidelines for 27 years. He is a member of several professional organizations for nutrition and laboratory science and sits on the editorial review boards for Alternative Medicine Review and Integrative Medicine - A Clinician's Journal. In conjunction with Dr. Richard Lord, Dr. Bralley wrote the landmark book Laboratory Evaluations in Molecular Medicine. He has served on the executive board for the Clinical Nutrition Certification Board and on the certification exam review board for International and American Association for Clinical Nutrition. He is also a clinical laboratory director licensed by state and federal laboratory agencies.
1. Bouchard MF, Bellinger DC, Wright RO, Weisskopf MG. Attention-deficit/hyperactivity disorder and urinary metabolites of organophosphate pesticides. Pediatrics. May 17 2010.
2. CDC. Organophosphorus insecticides: dialkyl phosphate metabolites. National Report on Human Exposure to Environmental Chemicals - Fact Sheet [Web page]. 2011. http://www.cdc.gov/exposurereport/OP-DPM_FactSheet.html. Accessed Oct. 30, 2011, 2011.
3. EPA. Organophosphate pesticides in food - a primer on reassessment of residue limits [Web page]. 2005. http://psych.umb.edu/faculty/adams/fall2005/US%20EPA%20-%20
Organophosphate%20Pesticides.htm. Accessed Oct. 30, 2011. (Bad link: Feb. 2012)
4. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. Jun 2009;30(4):293-342.
5. Slotkin TA. Does early-life exposure to organophosphate insecticides lead to prediabetes and obesity? Reprod Toxicol. Apr 2011;31(3):297-301.
6. Costa LG, Cole TB, Furlong CE. Polymorphisms of paraoxonase (PON1) and their significance in clinical toxicology of organophosphates. J Toxicol. Clin Toxicol. 2003;41(1):37-45.
7. Furlong CE, Cole TB, Jarvik GP, et al. Role of paraoxonase (PON1) status in pesticide sensitivity: genetic and temporal determinants. Neurotoxicology. Aug 2005;26(4):651-659.
8. Mackness B, Durrington P, Povey A, et al. Paraoxonase and susceptibility to organophosphorus poisoning in farmers dipping sheep. Pharmacogenetics. Feb 2003;13(2):81-88.
9. Akyildiz BN, Kondolot M, Kurtoglu S, Akin L. Organophosphate intoxication presenting as diabetic keto-acidosis. Ann Trop Paediatr. Jun 2009;29(2):155-158.
10. Eskenazi B, Bradman A, Castorina R. Exposures of children to organophosphate pesticides and their potential adverse health effects. Environ Health Perspect. Jun 1999;107 Suppl 3:409-419.
11. Eskenazi B, Rosas LG, Marks AR, et al. Pesticide toxicity and the developing brain. Basic Clin Pharmacol Toxicol. Feb 2008;102(2):228-236.
12. Swan SH. Semen quality in fertile US men in relation to geographical area and pesticide exposure. Int J Androl. Feb 2006;29(1):62-68; discussion 105-108.
13. Luoma J. Challenged conceptions: environmental chemicals and fertility [online document]. 2005. www.healthandenvironment.org/?module=uploads&func=download&fileId=66. Accessed Oct. 30, 2011, 2011.
14. CDC. Fertility, family planning, and reproductive health of U.S. women: data from the 2002 National Survey of Family Growth [online document]. 2002. http://www.cdc.gov/nchs/data/series/sr_23/sr23_025.pdf. Accessed Oct. 30, 2011, 2011.
15. CDC. National Survey of Family Growth [web page]. 2011. http://www.cdc.gov/nchs/nsfg.htm. Accessed Oct. 30, 2011, 2011.
16. Abdel Rasoul GM, Abou Salem ME, Mechael AA, Hendy OM, Rohlman DS, Ismail AA. Effects of occupational pesticide exposure on children applying pesticides. Neurotoxicology. Sep 2008;29(5):833-838.
17. Jurewicz J, Hanke W. Prenatal and childhood exposure to pesticides and neurobehavioral development: review of epidemiological studies. Int J Occup Med Environ Health. 2008;21(2):121-132.
18. Jajoo M, Saxena S, Pandey M. Transplacentally acquired organophosphorus poisoning in a newborn: case report. Ann Trop Paediatr. 2010;30(2):137-139.
19. Kristensen P, Irgens LM, Andersen A, Bye AS, Sundheim L. Birth defects among offspring of Norwegian farmers, 1967-1991. Epidemiology (Cambridge, Mass. Sep 1997;8(5):537-544.
20. Rojas A, Ojeda ME, Barraza X. [Congenital malformations and pesticide exposure]. Rev Med Chil. Apr 2000;128(4):399-404.
21. Heeren GA, Tyler J, Mandeya A. Agricultural chemical exposures and birth defects in the Eastern Cape Province, South Africa: a case-control study. Environ Health. Oct 4 2003;2(1):11.
22. Grandjean P, Harari R, Barr DB, Debes F. Pesticide exposure and stunting as independent predictors of neurobehavioral deficits in Ecuadorian school children. Pediatrics. Mar 2006;117(3):e546-556.
23. Bouchard MF, Chevrier J, Harley KG, et al. Prenatal exposure to organophosphate pesticides and IQ in 7-year old children. Environ Health Perspect. Apr 21 2011.
24. CDC. Fourth National Report on Human Exposure to Environmental Chemicals. Available at http://www.cdc.gov/exposurereport/pdf/FourthReport.pdf.
25. Barclay L, Sklar B. "Acceptable" lead level not low enough [online article]. 2003. http://www.medscape.org/viewarticle/452372. Accessed Oct. 30, 2011, 2011.
26. Curl CL, Fenske RA, Elgethun K. Organophosphorus pesticide exposure of urban and suburban preschool children with organic and conventional diets. Environ Health Perspect. Mar 2003;111(3):377-382.
27. Crinnion WJ. Environmental medicine, part 4: pesticides - biologically persistent and ubiquitous toxins. Altern Med Rev. Oct 2000;5(5):432-447.
28. Al-Attar AM. Physiological and histopathological investigations on the effects of alpha-lipoic acid in rats exposed to malathion. J Biomed Biotechnol. 2010;2010:203503.
29. Environmental Protection Agency. Lead in paint, dust and soil: renovation, repair and painting (RRP) [Web page]. 2011; http://www.epa.gov/lead/pubs/renovation.htm. Accessed Oct. 30, 2011, 2011.
30. Environmental Protection Agency. Toxic Substances Control Act (TSCA) [Web page]. 2011. http://epa.gov/agriculture/lsca.html. Accessed Oct. 30, 2011, 2011.