EXPLORATION 1:

Reading about chemicals in the popular press leads you to believe that chemicals are anthropomorphic, that is, they have the human like qualities of being good or bad. Some chemicals such as aspirin, antibiotics, vitamins and "medicines" are considered "good" whereas others can produce an extremely negative response. Pesticides as a class of chemicals have been perhaps the most emotive and maligned of all chemicals. Public concern, alarm and outcry have been pointed at these compounds since they are generally regarded in the popular press as being "bad" and threatening, versus anything "organic" which is natural and therefore inherently "good". Are these claims reasonable and the depictions reasonable and accurate?

Let's begin by defining a pesticide. The Miriam-Webster Dictionary notes that the word was first used circa 1925 and defines a pesticide as "an agent used to destroy pests" where pests are "a plant or animal detrimental to humans or human concerns (as agriculture or livestock production)". From these definitions, the importance of pesticides is placed in relation to the primacy of humans, society, agriculture and food. Pesticides have had a checkered history. Once being regarded as being god-sent and today being vilified as horrible poisons threatening man and the global environment. Both views have substance and must be measured within a specific context.

Four of the molecules that are pictured above are currently used or have been used as pesticides. More precisely, they are insecticides. The fifth compound could potentially be used as a pesticide, but it is too toxic to non-target organisms to be considered. By chemical definition they are all "organic" compounds since they contain covalently bonded carbon atoms in their structures. Two are synthetic (man-made) and the remaining three are natural, i.e. they are found in nature. To view these and other molecules in 2-D and 3-D and to be able to move them on screen will require Chime, a Web browser plug-in which provides visual renderings of molecular structures within the browser. Chime is only compatible with more recent versions of Netscape Navigator and Internet Explorer. A stand alone program that is similar to Chime is RasMol. It is useful for off-line viewing and the UCB version has a number of valuable features that are not incorporated in the current version of Chime.To download Chime or RasMol click on the active links which follow. A link to an excellent tutorial for Chime can be found at http://c4.cabrillo.cc.ca.us/chime/index.htm .

Chime and RasMol.

Drawing the cursor over the compound in the collection of molecular images above and clicking on them will link to their respective Chime viewable images. The center compound is malathion, a synthetic organophosphate. The other compounds, clockwise from upper left, are: saxitoxin, nicotine, physostigmine and DDT.

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Saxitoxin is a powerful neurotoxin that causes paralysis and death. It is associated with "red tides" and poisonings from eating shell fish: mussels, clams and scallops. The compound is highly toxic. In tests on lab mice, an oral dose of 263 micrograms (263 millionths of a gram) per kilogram of the animal's body weight is fatal to one half of the animals tested, which is referred to as the LD₅₀. An equivalent LD₅₀ for a person weighing 150 pounds is 18 milligrams (0.018 grams), which is about the mass of several grains of sand. The compound is so highly toxic that it is listed in the Chemical Weapons Convention List as a chemical agent scheduled for verification and control. Saxitoxin, a naturally occuring organic compound, is found in the salt water algae Gonyaulax catenella and Gonyaulax tamarensis. During warm summer months the algae "blooms" and saxitoxin becomes concentrated in shell fish which filter-feed on the algae, but saxitoxin does not affect the shellfish which are apparently tolerant. There seems to be an application of risk:benefit analysis in the age old adage of only eating shell fish during months that have an R in their spelling..........But, in our global society, how safe is it to eat rock oysters in Sydney, Australia in January, a month with an R in its spelling? If you want to know anything about Sydney Rock Oysters consult a local high school student's Web site: http://www.ozemail.com.au/~dkgsoft/oyster/oyster.html

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Nicotine, an organic natural product from Nicotiana sp., tobacco, is also a neurotoxin. It has been widely publicized in relation to smoking, chemical habituation and withdrawal. But, it is not widely recognized that nicotine has been used as a commercial insecticide for more than 75 years. Although it is approximately 1000 times less toxic than saxitoxin, it is still considered to be very hazardous to humans. Tobacco can contain up to about 10% nicotine by dry weight. Most college laboratory textbooks have removed experiments which involve nicotine, since nicotine is readily absorbed through the skin and is considered too toxic for instructional use. The Merck Index has the following cautionary information.

"Nicotine can be absorbed from the alimentary canal, the respiratory tract and intact skin. Percutaneous absorption of the free alkaloid is much more rapid than the acid salts. Local effects due to overexposure are burning sensation in mouth and throat, salivation, nausea, abdominal pain, vomiting and diarrhea. GI reactions are less severe but do occur after cutaneous and respiratory exposure. The major systemic effects are a transient stimulation and subsequent depression or paralysis of the CNS. Symptoms include agitation, headache, sweating, dizziness, auditory and visual disturbances, confusion, weakness and incoordination. At first respirations are deep and rapid, the blood pressure is high and the pulse is slow. CNS excitation may be evidenced by tremors or clonic-tonic convulsions. As depression develops, the pupils dilate, the blood pressure falls, and the pulse becomes rapid and irregular. Faintness, prostration, cyanosis and dyspnea progress to collapse. Death from paralysis of respiratory muscles usually follows shortly after collapse."

Would this statement be more powerful to a smoker than the caution that is printed on cigarette packages?And yet, nicotine can be used therapeutically. It has offered a better treatment for Tourette's syndrome and has shown promise in treating other disorders of the brain. (C&EN, pp. 23-26, March 27, 2000)

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Physostigmine is a natural product, which is isolated from Calabar beans obtained from Physostigma venenosum, a vine found in West Africa and introduced to Brazil and India. It has been reported that physostigmine helps with long term memory and improves some of the memory loss related to Alzheimer's disease because it builds high concentrations of a neurotransmitter, choline, through the inhibition of an enzyme, acetylcholinesterase. (For the structures of four new compunds being developed to treat memory loss in Alzheimer patients see: http://ep.llnl.gov/msds/pdb/pdb-structures.html.) Insects also use this enzyme neurologically and inhibiting it can result in death. Commercial insecticides have been developed which mimic physostigmine but are structurally much simpler such as carbaryl, a substituted naphthyl derivative

Exercise: #2)

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You can see that 3-D structural models relate a great deal of visual information but have their limitations. They are visual renderings that represent an idea of what molecules should look like if you could actually see them. You cannot generate these models with paper and pencil as you can 2-dimensional drawings. A computer with special software is necessary. Whereas 2-dimensional drawings are convenient and most useful in quickly communicating structural information. However, they too have limitations, particularly in portraying the spatial arrangement of atoms as molecular models. Taken together 3-D molecular models and 2-dimensional drawings are common, fundamental tools for modern organic chemists. They are also heavily used by scientists in molecular biology, biochemistry and many other disciplines.

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First and foremost, all chemicals including pesticides need to be considered within the context of their use. Paracelsus, a 16th century scientist/physician whose actual name was Philippus Theophrastus Bombastus von Hohenheim, and who is still rembered as a favorite son in Salzburg, Austria where he lived and died, is quoted as saying, "the dose is the poison". There is the possibility that any chemical can cause harmful effects including a molecule as indespensible and seemingly innocuous as water. Water can have deadly effects if administered too quickly without balancing salts on a cellular level in cases of severe dehydration. Also, quite astonishingly water has been reported as the cause of death in a suicide, in which the vicitim self-administered by iv a large enough amount of plain water to cause death. There are examples where toxicity is so magnified that certain compounds become devasting weapons of war as with VX, a "nerve gas" stockpiled by Iraq that is twenty times more toxic than saxitoxin and also on the Chemical Weapons Convention List. Breathing a few drops of VX can cause death, whereas malathion, another organophosphate, is considered to be non-toxic to moderately toxic. A lethal dose would be equivalent to eating about a quarter pound hamburger.

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Exercises:

#3) Calculate how many grams of VX is potentially lethal to a 150 lb person. Its toxicity has been reported as 15 micrograms per kg of animal weight in tests on rabbits.

#4) Atropine is an antidote against VX. It was carried in syrettes by allied troops under threat of attack during the Gulf War. The troops were to adminster it to themselves intramuscularly in the event of a gas attack. How much atropine would a soldier need to inject into themself in order to counteract the effects of VX in question #3? (Assume the stoichiometry of the biochemical de-toxification reaction is 1:1.)

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Compare the structure on the left of Atropine to the structure on the right, a neurologically active Compound C. Note any similarities in the structure and function. [If Chime is installed and images are not visible below, try the link: Exercise #4.]

Compound C is cocaine. Do you think that there risk in using the atropine antidote? Are you afraid of needles? Could you inject yourself? How much atropine would you administer to yourself if you were exposed to VX? Would you have time on a battlefield under fire to calculate an appropriate dose?

Compare the structures of malathion on the left and VX on the right. Draw their respective structures. What is different in the bonding arrangements to the phosphorus atom in the respective molecules? Consult the periodic table and compare oxygen and sulfur. Would you expect two compounds which have similar structures, but one with sulfur and the other with oxygen, to have similar biological properties?

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Malathion is considered to be generally safe and is widely used in insect control. California and Florida have sprayed the compound intermittently over wide areas including residences in an effort to control the Mediterranean fruit fly which could devastate billion dollar agricultural industries in these states. There are risks attendant to the use of any chemical and the issue becomes whether those risks are manageable and worth taking. The assessment of risk is currently taken into account in the regulation of pesticide use in the U.S. under a Federal law, FIFRA (Federal Insecticide Fungicide and Rodenticide Act and its amendments). This law empowers the EPA (Environmental Protection Agency) to register pesticides. The agency can ban or limit use to specific crops and applications. The scientific determination of risk:benefit is a key part of the EPA's decisions on the registration, sale and use of pesticides. The EPA approves pesticide labels which are legal documents. Use of pesticides outside of the label specifications is in violation of federal law, but there have been no know prosecutions of homeowners who have never read the product labels and have mis-used pesticides.When pesticide residues are found on food, the Food and Drug Administration (FDA) has the authority to set regulatory standards, and the FDA also applies risk:benefit analysis in their determinations. Pesticides can be banned on certain crops depending on their presence and toxicity. Both the FDA and EPA generally apply 100 to 1000 fold safety factors in their risk calculations.

From 1925 until in the 1970s the operative word in the definition of pesticide was "destroy". The objective being to destroy any plant, insect or other animal that was detrimental to humans. Until World War II, pesticide applications included natural, non-synthetic materials such as arsenicals, petroleum oils, nicotine, pyrethrum, rotenone and sulfur. Most pesticides were not that widely used due to limited supplies, but the availability of chlorine and caustic soda (NaOH) produced from the electrolysis of brine (NaCl aq) changed that. Chlorination linked with other, new chemical reactions produced a large group of synthetic organochlorine compounds which were biologically tested for efficacy, i.e. to see if they killed pests. The most notable was an organochlorine insecticide, DDT. Although first prepared in 1874, Dr. Paul Muller, an entomologist working with a large Swiss chemical company, discovered in 1939 that DDT was highly effective in destroying the mosquito species that transmitted malaria and yellow fever to humans as well as killing many other insect-vectors for other diseases such as typhus and plague . This discovery was acclaimed worldwide, and in 1948 Dr. Muller was awarded the Nobel Prize in Medicine and Physiology. Since the 1940s, DDT has been used throughout the world. It is estimated that more than 4 billion pounds of DDT have been made and used.

However, in the United States on June 14, 1972, the Environmental Protection Agency (EPA) ordered DDT sales terminated by the end of 1972. This decision followed seven-months of hearings and concluded six years of litigation against DDT. What caused the fall of a "miracle", "good" chemical which produced a Nobel prize? DDT's downfall is coincident with the rise of an appreciation of what harm bioactive chemicals can do to non-target organisms and the environment, which was not originally considered nor immediately evident in many chemicals of the 1940's and 1950's. After a decade of use many insect species developed resistance to DDT, and DDT was discovered to be highly toxic to fish. Over the next decade other scientific data raised a spectre over DDT.

DDT is highly soluble in lipids (fats and oils) and almost insoluble in water, approximately 2 ppb (parts per billion), and DDT accumulates in the fat of animals due to its high lipophilicity and its slow metabolic degradation. The biological half-life of DDT and its dehydrohalogenated form DDE is approximately eight years. This would be the amount of time it takes an animal to remove one half of the compound(s) from its system. Also, residues of DDT and DDE appeared in food products that had been sprayed with DDT, and DDT was found in alarmingly high levels in many animals including fish, birds, and mammals, as well as in some plants. The wide presence of DDT and DDE in many ecosystems and the biomagnification in the food web where species at the top of the food chain such as man could have potentially high levels caused large concern. DDT's detrimental effects were particularly noticed in the decline of predatory birds: hawks, eagles, falcons and the California condor. These predators are at the top of the food chain and were believed to be affected by the accumulation of DDT in their fat cells. Research had shown that the Californian condor and peregrine falcon with high concentrations of DDT and DDE produced thin egg shells which resulted in fewer surviving offspring. These two species that thrived before the use of DDT were near extinction and are still severely challenged more than twenty five years after DDT's discontinued use.

The environmental movement helped generate public awareness and produced an outcry against the use of DDT. An important publication was Rachel Carson's book, Silent Spring, which was released in 1962. A Web-review in Amazon Books (http://www.amazon.com/) notes..... " (It) offered the first shattering look at widespread ecological degradation and touched off an environmental awareness that still exists. Rachel Carson's book focused on the poisons from insecticides, weed killers, and other common products as well as the use of sprays in agriculture, a practice that led to dangerous chemicals to the food source. Carson argued that those chemicals were more dangerous than radiation and that for the first time in history, humans were exposed to chemicals that stayed in their systems from birth to death. Presented with thorough documentation, the book opened more than a few eyes about the dangers of the modern world and stands today as a landmark work."

The use of DDT in the U.S. ended in 1973. The last operational chloral plant, a key DDT raw material, was in Long Beach, California. It was closed, dismantled and shipped to India where it was re-assembled and is still in use today. DDT is currently banned from use in most countries throughout of the globe with the exception of a few countries such as India and Mexico. Why are some countries still using DDT? The World Health Organization (WHO) estimated that during the period of DDT's use approximately 25 million lives were saved. An estimated 15 million from malaria alone. DDT is very inexpensive to produce from the reaction of chlorobenzene, sulfuric acid and chloral. Countries that have relatively large populations, poverty and endemic diseases such as malaria cannot afford other methods of vector control and choose to protect human life over other animals and the environment. Mexico hopes to end DDT's use over the next ten years. India has not announced any plans to discontinue the use of DDT.

DDT and DDE are displayed above. Save .pdb files of DDT and DDE to your desktop. Using RasMol, which can be downloaded at: http://mc2.cchem.berkeley.edu/Rasmol/. Click on the RasMol bond distance feature to determine the C-C interatomic distance between the non-ring carbons in DDT and DDE. Record those values and explain why one is shorter than the other. Provide a mechanism for the conversion of DDT to DDE.

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In the 1930s and 40s while the organochlorine compounds were being researched, another class of insecticides, the organophosphorus compounds were also being developed. Gerhard Schrader, a chemist with Bayer, the gigantic German company of aspirin fame, synthesized TEPP and Schradan. These compounds were used for several years, but both were replaced with organophosphates that were less toxic and worked better in insect control. Also, during World War II, Bayer chemists synthesized a number of similar compounds as weapons of war. These "nerve gases" included sarin, soman, and tabun. The inital discovery of severe toxicity and potential as a weapon was made in search of substitutes for nicotine, which was heavily used as an insecticide but in short supply in Germany. Sarin was used in a terrorist incident in the Tokyo subway in 1995 in which a number of people died and many were injured.

After World War II, Bayer and other companies began to introduce a large number of organophosphorus compounds into the marketplace for insect control. These compounds offer an advantage over DDT in that they break down fairly quickly in the environment. Many of them such as malathion have a long history and are still widely used in home and agricultural applications today. The difficulty with organophosphates (OPs) is that they are neurotoxic due to their effects on acetycholinesterase, and unfortunately as you saw in the mode of action of physostigmine and the methyl carbamate insecticides this enzyme occurs in humans as well as in insects. Malathion as an OP inhibits acetylcholinesterase much less than others which is a factor in its relative safety and wide spread use.

Plant nurseries, hardware stores and department stores with a home and garden department will likely carry pesticides including malathion. One pint (473 mL) of Malathion 50 was recently purchased. It cost $10.50 and contained 50% by weight of [(Dimethoxyphosphinothioyl)thio]butanedioic acid diethyl ester and 50% inert ingredients. Calculate the cost per gram of malathion active ingredient in the product? The density of the product is 2.4 g/mL

Medfly:USDA Animal and Plant Health Inspection ServiceIn

Florida, the cost to eradicate a Mediteranean fruitfly infestation in the summer of 1997 was estimated to be $20 million. The largest portion of the costs were for malathion and the flight time of helicopters and airplanes to aerially apply the insecticide. Ray Gilmer, director of communications for the Florida Fruit and Vegetable Association, was quoted as saying, "If there's anything we've learned from this experience, it is that no matter what the cost of consistent regular field inspection for medfly it's worth it." Considering that Florida's citrus industry, worth an estimated $10 billion, is seriously threatened by the fruit fly, $20 million is easily justified. The July 19, 1997 issue of the Economist reported: "This effort itself has brought controversy. Many of the affected areas include rich and sprawling suburbs east of Tampa Bay, where residents do not like to see their playgrounds, lakes and even their children doused with spray in the wake of low-flying aircraft. Although government regulators insist that Malathion is relatively benign to humans and pets, environmental regulators have measured its presence in swimming pools, lakes and rivers at many times the level officially considered safe." The USDA's program to eradicate the medfly calls for the use of minimal amounts of malathion through baited traps as well as aerial application. It also uses sterilized males that are released into the environment to compete with beeding males.

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The world pesticide market is estimated at approximately $30 billion ($3.0 x 10¹⁰). Although it seems large, it is a small amount compared to the global value of agricultural commodities which is worth trillions of dollars ($ 10¹²)! The Florida citrus market is very small when compared to the total, global agricultural market. However, it is very important to the people of Florida and the state's economy since it translates to jobs and economic well being. It also relates to many of us, since much of the orange juice on the breakfast tables in the U.S. comes from Florida. The question is: "Is it important enough to warrant use of pesticides?". The value of pesticide use is measured by what is saved versus what would be lost due to pest damage, if pesticides were not used. There are many estimates of this value crop by crop and much debate over the risks attendant with pesticide use relative to the economic benefits. Risk and benefit cannot be measured directly and calculations of risk:benefit typically involve many assumptions and complicated formulas which leads to a great deal of debate.

A comprehensive crop management program has been developed that minimizes pesticide usage through an approach called Integrated Pest Management (IPM). The aim of the program is to advocate the best farm practices for a specific problem which may or may not include use of a pesticide. However, at present there are no alternatives other than pesticides to deal with certain problems. IPM recognizes that in these cases it is in everyone's interest to make sure that no more than an absolute minimum amount of pesticide is used which offers a cash advantage to the grower, lowers environmental impact and lessens the likelihood of pests building up resistance.

For further reading on these and related topics see:

• Glossary of Pesticides: http://vm.cfsan.fda.gov/~frf/pestglos.html
• Center for Integrated Pest Management (CIPM): http://cipm.ncsu.edu/index.html
• Integrated Pest Management World Textbook: http://ipmworld.umn.edu/
  

A personal risk/benefit test:

The issue of pesticide toxicity, exposure and regulation is complex and has many interrelated personal, social and economic considerations. At the heart of pesticide exposure in the Florida-medfly outbreak is that it was involuntary. The government decided that the benefits outweighed the risks and it was beyond the control of the residents of Tampa Bay who were exposed to the pesticide to alter the decision. Let us examine a case where you do have a choice, that is in the food you buy and eat. Some farm produce is pesticide treated and other is "organic", in this case meaning pesticide free. Which do you buy? Have you made a conscious, informed decision in your purchases and determined whether it is worth the extra cost or not to buy "organic" and avoid the risk of pesticide exposure?

Go to a grocery store that has both "organic" and regular produce. Select FOUR items that are available in both types and record their prices. Make sure that the prices are on the same basis, i.e. $/lb, $/bunch, $/dozen, etc. Record the difference in each of the prices and the totals. Calculate the percent difference. This is also equal to the amount that you would be paying extra per $100 of produce. Is it worth it to you and will your group buy organic?