Martina Unutzer and Amanda Lyon Chem 165 AA Organophosphates: Agricultural Necessity or Environmental Toxin?

Introduction Agricultural chemicals and pesticides are a major part of the chemical industry. The pesticides produced support agriculture on a massive scale, and have transformed how food is grown. However, pesticides are essentially toxins, and there is serious debate over whether the benefits of pesticide use outweigh the risks. Organophosphates have become a popularly used insecticide in the last few decades, replacing some older insecticides and supporting an expanding agricultural industry. This report examines how organophosphates work and affect the environment and presents the medical, environmental, and legal issues that are part of the debate over the safety and use of organophosphate insecticides. Chemical Structure Organophosphates consist of a phosphorous atom bonded with three oxygen atoms that link to different organic groups and double bonded to a sulfur or oxygen atom. The different R groups determine the specific compound.1

Figure 1: Organophosphates consist of a phosphorous double bonded to an oxygen or sulfur atom. They contain three groups (R) linked to the phosphorous center by an oxygen atom.

One of the most common organophosphates is chlorpyrifos. Chlorpyrifos has two ethyl groups and a 2,3,5-trichloropyridine group connected to the phosphate atom.2

Figure 2: Structure of chlorpyrifos, which is typically administered as a spray on corn, cotton, almonds to repel insects. The United States typically applies 20-24 million pounds per year.2

Organophosphate compounds are generally synthesized from phosphoric acid, which already has a P=O bond. The three R groups come from alcohols and react in an esterification process to bond with the central phosphorous atom.3

Figure 3: Phosphoric acid and alcohols react to form organophosphates in an esterification process.

History Organophosphates were first developed as chemical weapons in World War II. The German chemical company I. G. Farben created three organophosphate compounds which were eventually used as nerve gases. Both sides of the war pursued organophosphate research. In 1932, the Berlin chemist Lange published a paper describing his accidental discovery of toxic diethylphosphorofluoridate vapors and the potential use of these compounds as insectides. British scientists and American scientists at the Edgewood Arsenal took note of this discovery

and began testing toxic alkyl phosphorofluoridate compounds. Both sides ended up pursuing similar research, which they did not fully realize until after the war when these secrets were finally revealed.4 After the war, the poisons were seen as potential insecticides, and these compounds were developed throughout the 1950s. In 1965, Dow Chemical Company began producing the organophosphate chloropyrifos. Soon after its introduction, several organochloride insecticides were banned by the EPA, including DDT in 1972 and chlordane in 1988. Organophosphates such as chloropyrifos took advantage of the suddenly empty market, and quickly became a popular and widely used agricultural and household chemical.4 Legal The production and use of organophosphates have led to a constant legal battle between Dow Chemical Company and the EPA and other individuals. In 1994, Dow and the EPA clashed over the contents of a Duraban (chlorpyrifos) brochure. The EPA accused Dow of making deceptive claims about the safety of the chemical, and Dow discontinued the brochure. In 1995, Dow was fined $876,000 for failing to share reports of adverse effects of chlorpyrifos with the EPA in a timely manner. The company had collected 288 reports from consumers about negative health effects linked with use of Duraban. The first compromise between Dow and the EPA occurred in 1997, when Dow agreed to stop putting chlorpyrifos in a few residential use products.5 Dow still adamantly maintains that chlorpyrifos is safe for humans and animals in the concentrations they are exposed to, and often refuses to settle lawsuits on principle. Many individual plaintiffs have brought lawsuits against Dow for health damage from chlorpyrifos exposure, but most of these suits are not successful; 15 out of 16 lawsuits in 1999 were decided

in favor of Dow. One exception to Dows principle not to settle was a 1995 lawsuit involving a 5 year old boy who was paralyzed and respirator dependent. Dow settled because they believed that no jury would side with them against an injured child, but they again stated that they would continue refusing to settle any future lawsuits. In 2006, the EPA finalized their decision to ban residential organophosphate use and to somewhat limit other uses, such as application on golf courses, but organophosphates are still a widely used agricultural insecticide.5 Medical Effects and Biological Reactions Organophosphates are neurotoxins, harmful to all animals (including humans) in significant quantities, but particularly toxic to insects, which lack the capacity to break down and process the compounds1. They prohibit the enzyme cholinesterase from functioning properly.

Figure 4: Simplified model of an enzyme/substrate reaction. An inhibitor takes the place of the substrate and prevents the reaction of the enzyme and substrate.

Cholinesterase is a key enzyme for the nervous system, and is critical for normal control of nerve impulse transitions from nerve fibers to muscles cells throughout the body. This process works like a traditional catalytic and enzymatic reaction where the inhibitor binds to the enzyme, which does not allow the substrate to bind and thus inhibits the mechanism from proceeding. The organophosphate compounds are inhibitors, attacking the serine site on the acetylcholinesterase enzyme. The organophosphate acts similarly to the acetylcholine substrate and binds with the acetylcholinesterase enzyme, preventing the enzyme from binding with other compounds and

carrying out its necessary function in the body.6 Through this process, organophosphates can cause muscle contraction and secretion. Decreased muscle coordination can also result, and death can be caused by pulmonary secretions and respiratory failure7. The biological half-life of organophosphates in the blood stream is approximately 24 hours and increases to 60 hours when stored in fat.8 Once in the body, organophosphates may be stored from a period of days to a period of months. However, organophosphates are nonpersistent insecticides because they can be broken down into harmless products.1 The liver must break down all of the toxic material through the process of hepatic metabolism.6

Figure 5: reaction of an organophosphate (in this example, chlorpyrifos) during hepatic metabolism in the liver.

In the reaction in Figure 4, an oxygen atom replaces the sulfur atom in the chlorpyrifos. The compounds are converted from thions (with a P=S bond) to oxons (O=S), which can be broken down by liver microsomes in the body. To break down the oxons, the oxons are hydrolyzed into a primary and leaving group and form dialkyl phosphates, which can be excreted from the body.9

Figure 6: The hydrolysis of an organophoshpate (chlorpyrifos) to form DEP and TCP in the body.

This reaction takes place in the liver and unfortunately allows the organophosphate to be a more potent inhibitor of the cholinesterase enzyme. If the process is relatively slow the toxins may be stored in fat cells in the body before excretion, thus producing an even longer exposure to the toxicity. This result is known as delayed toxicity because toxins are stored in fat cells and are released later and at a slower rate. The hydrolysis reaction in Figure 5 is important for scientists because it allow the measurement of chemicals digested in the body. Professionals can measure the chemical amount of organophosphates in the body, and the type of organophosphate because the leaving group is also eliminated from the body in urine.6 In tests done on rats the LD50 (the amount needed in a population to cause a 50% death rate) ranged from 3 to 8 mg/kg for an oral dose, which is incredibly toxic.6 Toxicity depends on the intake of organophosphates, which may include ingestion, inhalation, and dermal contact through the skin.10 Symptoms usually appear fastest in inhalation, followed by ingestion and finally topical contact. Some mild symptoms include chest tightening, shortness of breath and stomach cramps. Recent studies have shown that persistent headaches, blurred vision, muscle weakness, depression, memory and concentration problems, and development of intolerance toward certain chemical odors are also reoccurring symptoms from mild exposure to organophosphates.6 In an article published in 2010 by CNN, the reporter Sarah Klein from Health.com made known the effects of organophosphates ingested through food by children and

the relationship it has with an increase of the likelihood of ADHD.11 The study focused on a random group of children, and involved a urine test to analyze the amount of organophosphates present in the body. Klein suggests that the biggest source of ingesting these chemicals comes from commercially grown food, and the amounts of food affected range from 17%-28% in fruits and vegetables. When reviewing toxicity and effects of organophosphates on the body, it is important to remember that the class of toxic materials this encompasses is very vast. While some of the tested organophosphates are completely capable of inducing comas and even death, it is wrong to assume that all organophosphates can do this with the same dosage. This does not imply that some organophosphates are not toxic; they all are toxic but have different lethal doses. They are all classified as organophosphates based on structure and targeted usages. All of these compounds are toxic, but are toxic on a wide range of dosages. Agricultural Effects Organophosphates are designed to kill any living species of insect that comes into contact with the chemical through paralysis of the central nervous system, just like the chemical affects humans. The chemicals are incredibly efficient at killing pests; the problem arises in the fact that they kill all species, even ones that prey on the targeted pests. Recently, companies around the world including the United States have launched a smallscale campaign intended to raise awareness about bee populations. Bees contribute an incredible amount in the ecological processes in the environment through pollination. However, the increase in the use of pesticides, especially organophosphates, has caused a sharp decline in bee populations worldwide.

On a commercial level, organophosphates are incredibly well designed to reduce costs of production and to increase the amount of product generated, and to produce this food at a lower cost. On average, the farmer receives a $3-$5 return on crop yield with a $1 investment in pesticides.1 Organophosphates are therefore very practical and reliable in large-scale operations. On the other side, organophosphates can induce debilitating effects on the ecological and agricultural systems. First, organophosphates are broad pesticides, which kill any insect that comes into contact with the chemical. This means that the chemicals will also kill natural predators of the pest insects. Over prolonged and consistent exposure to these chemicals, the insects will increase their immunity. Simply put, the usage of pesticides must increase to maintain the current rate of killing insects, and as more organophosphates are put into the agricultural process there will be more chemicals on food and ingested by humans. Environmental Effects Once organophosphates enter the environment, they degrade and are passed along to other compartments within the environment such as groundwater, precipitation, air, and sediment. Generally, degradates are more polar and water soluble than the original organophosphates that are put into the environment. These features allows the degradates to be more easily transferred from various parts of the environment into different components. Mandatory tests are required for degradates that have a concentration greater than 10% of the original parent concentration, but the tests are short-term and thus are not comprehensive, as it slowly starting to be proven that sustained toxicity in the environment may be far more dangerous than a one-time exposure. Furthermore, organophosphates have a mean parent halflife around 45 days. This is the length of time that the pesticide remains in the environment before degrading, where it still remains in the environment but in a different form (when

synthetic materials degrade in the environment). For example, chlorpyrifos in the environment undergoes hydrolysis with a half-life of around 2,118 days, which is well above the limit that categorizes toxins as possibly unsafe in groundwater. The other main environmental concern that is rising in the increasing research on organophosphates is that they exist as enantiomers because most are chiral. While tests will only read that the chemical formulas and weights are the same, they cannot determine the structure of the molecule, and most pesticides are being used under this false pretense. Chiral molecules will react and interact differently between the various enantiomers, which has been seen through various experiments measuring the enantiomer ratios in the liver of polar bears. These ratios vary dramatically from region to region as the different organophosphates vary. Organophosphates typically contain two enantiomers and very little is known about the enantioselectivity of the compounds in the environment.12 Conclusion Organophosphates are very effective inhibitors on the nervous system, and this property has been exploited for both beneficial and harmful use. Insecticides such as chlorpyrifos effectively kill pest insects and allow higher farming yields and lower cost food production. However, this potency is not limited to only pests. These compounds act in a similar manner as neurotoxins on other animals, including predators to the pests, beneficial insects such as bees, and humans who are exposed to the compounds in food or environmental applications. Though the exact effects and danger of different doses is debatable and contested, organophosphates can cause significant biological harm in high enough doses. Because of this danger, organophosphate use has become somewhat regulated and restricted, but large quantities of the compounds are still used agriculturally. If organophosphates are used as the effective insecticides that they are,

the danger to other organisms, which can be significant, must be carefully determined and weighed against possible benefits that these chemicals might offer.

Works Cited
1

Sereda, Grigoriy A. Chemistry of Biosphere. University of South Dakota website. http://people.usd.edu/~gsereda/bio.ppt (accessed May 6, 2011).

Chlorpyrifos - Toxicity, Ecological Toxicity and Regulatory Information. PAN Pesticide Database. http://www.pesticideinfo.org/Detail_Chemical.jsp?Rec_Id=PC33392 (accessed May 19, 2011).

Eggling, Sue, Clackamas Community College. Phosphate Esters. http://dl.clackamas.cc.or.us/ch106-04/phosphat.htm (accessed May 24, 2011).

Tvedten, Stephen. History of the Development of Organophosphate Poisons. http://www.getipm.com/bestcont/history-of-organophosphates.htm (accessed May 6, 2011).

5 6

Morris, Jim. The stuff in the backyard shed. U.S. News & World Report, Oct 1999, pp 64-68. Eddleston, M.; Szinicz, L.; Eyer, P.; Buckley, N. Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials QJM: An International Journal of Medicine. 2002, 95(5), 275-283.

Reigart, John Rout; Roberts, James R. Organophosphate Insecticides. In Recognition and Management of Pesticide Poisonings, 5th ed.; U.S. Environmental Protection Agency and National Pesticide Information Center, Washington, D.C., 1999; pp 34-47.

US Environmental Protection Agency. EPA Policy for Managing Risk to Workers from Organophosphate Pesticides (OPs) | Pesticides | US EPA. http://www.epa.gov/pesticides/factsheets/opworkers.htm (accessed Apr 21, 2011).

Barr, Dana B.; Bravo, Roberto; Weerasekera, Gayanga; Caltabiano, Lisa M.; Whitehead, Ralph D.; Olsson, Anders O.; Caudill, Samuel P.; Schober, Susan E.; Pirkle, James L.; Sampson, Eric J.; Jackson, Richard J.; Needham, Larry L. Concentrations of Dialkyl Phosphate Metabolites of Organophosphorus Pesticides in the U.S. Population. Environmental Health Perspectives. 2004, 112.2, 186-200.

10

Illinois Department of Public Health. Organophosphates: IDPH Emergency Preparedness. http://www.idph.state.il.us/Bioterrorism/factsheets/organophosphate.htm (accessed May 1, 2011).

11

Klein, Sarah. Study: ADHD Linked to Pesticide Exposure. CNN.com. http://www.cnn.com/2010/HEALTH/05/17/pesticides.adhd/ (accessed Apr 21, 2011).

12

Biological Sciences - Environmental Sciences: Liu, Weiping; Gan, Jianying; Schlenk, Daniel; Jury, William A. Enantioselectivity in environmental safety of current chiral insecticides. PNAS. 2005, 102(3), 701-706.

13

Aminetzach, Yael T.; Macpherson, J. Michael; Petrov, Dmitri A. Pesticide Resistance via Transposition-Mediated Adaptive Gene Truncation in Drosophila. Science. 2005, 309(5735), pp 764-767.

14

Boxall, Alistair B. A.; Adams, Craig D. Occurrence of Transformation Products in Environmental Chemistry. In Transformation Products of Synthetic Chemicals in the Environment. Springer: Berlin, 2009. pp 100-02.

15

Horton, Megan K.; Jacobson, J. Bryan; McKelvey, Wendy; Holmes, Darrell; Fincher, Betty; Quantano, Audrey; Diaz, Beinvendida Paez; Shabbazz, Faye; Shepard, Peggy; Rundle, Andrew; Whyatt, Robin M. Characterization of Residential Pest Control Products Used in Inner City Communities in New York City. Journal of Exposure Science and Environmental Epidemiology. 2010, 21, pp 291-301.

16

PCO Directory: Non-Toxic Pest Management. Beyond Pesticides. http://www.beyondpesticides.org/infoservices/pesticidefactsheets/toxic/chlorpyrifos.htm (accessed May 19, 2011).

17

Slotkin, Theodore A.; MacKillop, Emiko A.; Ryde, Ian T.; Tate, Charlotte A.; Seidler, Frederic J. Screening for Developmental Neurotoxicity Using PC12 Cells: Comparisons of Organophosphates with a Carbamate, an Organochlorine, and Divalent Nickel. Environmental Health Perspectives. 2007, 115(1), pp. 93-101.

18

US Environmental Protection Agency. Chlorpyrifos Facts. http://www.epa.gov/opp00001/reregistration/REDs/factsheets/chlorpyrifos_fs.htm (accessed May 1, 2011).

19

US Environmental Protection Agency. Reregistration Status for Organophosphates | Pesticides | US EPA. Web. 21 Apr. 2011. http://www.epa.gov/pesticides/reregistration/status_op.htm (accessed Apr 21, 2011).

20

U.S. Geological Survey. Iowa District.USGS Iowa Water Science Center. 07 Apr. 2011. http://ia.water.usgs.gov/nawqa/factsheets/fs-116-97.html (accessed Apr 7, 2011).