How is a very small quantity of poison able to kill a large organism?

How is a very small quantity of poison able to kill a large organism?

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Take cyanide for example: it prevents mitochondria from producing energy in form of ATP but, in the process, it binds with it and hence it's spent.

It's theorized that half a gram of cyanide can kill an average adult human. How is this possible? There surely is more than half a gram of mitochondria in an adult human. So, if cyanide molecules bind and hence get spent so fast, how are they able to kill so many cells so fast and continuously?

Is it something to do with the amount of molecules in half a gram of cyanide being several times higher than the amount of cells in one gram of human tissue?

"Cyanide" doesn't refer to just one compound, but given the lethal dose you mention of "half a gram" you are probably referring to potassium cyanide, with a molecular weight of about 65g/mol, so 0.5 gram is about $10^{22}$ molecules. Potassium cyanide becomes hydrogen cyanide in the stomach, and hydrogen cyanide is the gas (at body temperature) that causes toxic effects.

The toxicity of cyanide containing compounds is because they bind with high affinity to cytochrome c oxidase, an enzyme that is part of the mitochondrial electron transport chain. The result is that electrons cannot be efficiently transferred to oxygen molecules. The effect is roughly the same as if oxygen was not present in the inspired air.

$10^{22}$ is a huge number. That's about 250 million molecules per human cell in an adult (taking # of human cells from Bianconi et al). Even so, it isn't likely that cyanide molecules be perfectly bound at every molecule of cytochrome c oxidase, just that there is enough to cause massive brain damage or stop the heart.

By comparison, cyanide is not even close to the most toxic substance. Toxins that target neurotransmission can be much more potent. For example, the IV LD50 for botulinum toxin is about 2 ng/kg, so something like 125 ng for an average adult, equaling only $5 imes10^{11}$ molecules.

Dose of exposure

The amount of chemical to which a person is exposed is extremely important. The chemical acts at a certain site, called the active site, triggering a biological response in a target tissue. Because the biological effect is caused by the presence of the chemical at the active site, the higher the concentration of the chemical at the site, the greater the response. This is the case with all known poisons, a phenomenon called the dose–response relationship.

The dose–response curve is sigmoid, with the linear portion between approximately 16 percent and 84 percent. To compare the potency of chemicals causing similar responses, the dose that produces a biological response in 50 percent of the subject group is chosen, because it can be calculated with the least chance of error. If the biological response is mortality, the dose that kills 50 percent of the exposed population is known as the lethal dose 50, or LD50. Toxicity ratings for chemicals are based on their LD50s. The toxicity rating indicates the amount of chemical required to produce death, but it should be remembered that all chemicals can kill. Thus, all chemicals are toxic. More important than the toxicity of a chemical is its hazard or risk of usage, a concept that incorporates exposure to dosage. For example, botulinum toxin is not especially hazardous, even though it is supertoxic, because food is well-preserved, keeping the exposure or dose very low. In contrast, ethanol (alcohol) is hazardous even though it is not very toxic, because some people have a tendency to use it to excess.

What is arsenic poisoning?

Arsenic poisoning, or arsenicosis, happens when a person takes in dangerous levels of arsenic. Arsenic is a natural semi-metallic chemical that is found all over the world in groundwater.

Intake can result from swallowing, absorbing, or inhaling the chemical.

Arsenic poisoning can cause major health complications and death if it is not treated, so precautions exist to protect those who are at risk.

Arsenic is often implicated in deliberate poisoning attempts, but an individual can be exposed to arsenic through contaminated groundwater, infected soil, and rock, and arsenic-preserved wood.

However, arsenic in the environment is not immediately dangerous, and it is rare to find toxic amounts of arsenic in nature.

Share on Pinterest The effects of arsenic are dangerous, but overexposure to it is very rare.

Arsenic is a naturally occurring, metalloid component of the Earth’s crust. Minuscule quantities of arsenic occur in all rock, air, water, and soil. A metalloid is a substance that is not a metal but shares many qualities with metals.

The concentration of arsenic may be higher in certain geographical regions. This could be a result of human activity, such as metal mining or the use of pesticides. Natural conditions can also lead to a higher concentration.

It can be found combined with other elements in different chemical compounds. Organic forms of arsenic also contain carbon, but inorganic forms do not. Arsenic cannot be dissolved in water.

Inorganic arsenic compounds are more harmful than organic ones. They are more likely to react with the cells in the body, displace certain elements from the cell, and change the cell’s function.

For example, cells use phosphate for energy generation and signaling, but one form of arsenic, known as arsenate, can imitate and replace the phosphate in the cell. This impairs the ability of the cell to generate energy and communicate with other cells.

This cell-altering ability may be useful in cancer treatment, as some studies have shown it can send the disease into remission and help thin the blood. Arsenic-based chemotherapy drugs, such as arsenic trioxide, are already in use for some cancers.

The symptoms of arsenic poisoning can be acute, or severe and immediate, or chronic, where damage to health is experienced over a longer period. This will often depend on the method of exposure.

A person who has swallowed arsenic may show signs and symptoms within 30 minutes.

If arsenic has been inhaled, or a less concentrated amount has been ingested, symptoms may take longer to develop. As the arsenic poisoning progresses, the patient may start experiencing convulsions, and their fingernail pigmentation may change.

Signs and symptoms associated with more severe cases of arsenic poisoning are:

  • a metallic taste in the mouth and garlicky breath
  • excess saliva
  • problems swallowing
  • blood in the urine
  • cramping muscles
  • stomach cramps
  • convulsions
  • vomiting
  • diarrhea

Arsenic poisoning typically affects the skin, liver, lungs, and kidneys. In the final stage, symptoms include seizures and shock. This could lead to a coma or death.

Passive Poisons vs. Militant Venoms

Many animals and plants are equipped with potent toxins to deter potential predators like us. The term used for such toxins depends on how they’re used. It’s kind of like how lawyers use the term “murder weapon” to refer to an object used to kill someone — a paperweight, a knife, or a shoe isn’t a murder weapon (or in two of those cases, a weapon at all) until its used to commit the crime. Well, toxins aren’t referred to as poisons or venoms until how they enter someone’s body has been taken into account. Some toxins act when ingested, absorbed through the skin, or inhaled such toxins are referred to as poisons . Others enter our bodies through wounds deliberately inflicted by the toxic species — those are venoms.

Because poisons must be eaten, rubbed on the skin, or breathed in, they’re somewhat “passive” toxins — for the most part, if you’re poisoned, it’s you who did something to cause it. You ate or touched something you really, really shouldn’t have, like an aptly-named poison dart frog, a pufferfish, or certain mushrooms.

The somewhat active role of the intoxicated in poisonings is what sets them apart from envenomations. It essentially boils down to who the aggressor is: the toxic species (venoms) or the one who suffers the effects of the toxins (poisons). Venomous animals and plants by definition are armed with physiological weapons to inflict their terrible chemical cocktails — they bring the toxins to you. It’s entirely possible the only thing someone did to cause an envenomation is unknowingly stray in the general vicinity of a venomous species (though there are certainly times when it’s totally the victim’s fault , and some defensively venomous species just sit and wait for you to impale yourself on them). Though it’s a bit oversimplified, this comic sums up the difference quite nicely:

The difference between poison and venom is why toxinologists cringe every time they see someone referring to a “poisonous snake.” Most snakes are perfectly fine to handle or eat (I hear they taste like chicken with the texture of fish — which, frankly, sounds delicious), presuming you don’t get stuck with the pointy bits in the process . There are even snakes that can kill you with their venomous bites that are considered delicacies in certain cultures’ cuisines … just ask Gordon Ramsay:

That said, there are exceptions to every rule. Yes, there are some poisonous snakes. The most well studied are the species in the genus Rhabdophis , which are both poisonous and venomous. R. tigrinus , for example, is able to sequester and store toxins from the toads it eats and secrete them on its skin to deter would-be predators. But if warning displays and even poison fail to send a message, the snake is also equipped with a potentially deadly venomous bite .

And then there’s even a third subcategory of toxins, for those who appreciate being as accurate as possible: toxungens. Outlined very succinctly by David Nelsen and his colleagues in their 2014 paper , toxungens are poisons that are aggressively wielded, like the squirting of poison by cane toads or spitting of venom by certain cobra species.

Since no wound is inflicted when the toxins are sprayed, they aren’t considered “venoms” in context, but the animals aren’t exactly waiting to be harassed, either. Because the toxic species is actively involved in the delivery of its noxious chemicals, but they aren’t making wounds, we give them a special category all to themselves.

So there you have it. Toxins are substances that cause harm in small amounts. There are three main types of toxins: venoms , poisons and toxungens , which differ based on route of delivery (see the table above). If an animal or plant possesses a toxic chemical cocktail, you can label them with the appropriate adjective(s) — venomous, poisonous and/or toxungenous.

And yes, there are many species which fit into multiple categories, such as poisonous and venomous Rhabdophis snakes or poisonous and toxungenous cane toads. In such cases, you can use whichever terms are most appropriate in context if you’ve just licked a cane toad to try and get high, for example, poison would be most appropriate word for what you’ve ingested. But if you poked it, and it squirted toxins into your eyes, then you get a gold star for calling the beast toxungenous.

Now that you know the right terminology, I encourage you to go forth and correct your friends, family, and coworkers! Though, I would caution you to do your best to be nice about it. You never know what toxins they might have access to …

Pick Your Poison—12 Toxic Tales

Bad things come in small packages. On August 14, 1996, Karen Wetterhahn, a toxicologist and professor of chemistry at Dartmouth College, spilled a drop, a tiny speck, of dimethylmercury on her left hand. Wetterhahn, tall, thin, intense, was an expert on how toxic metals cause cancer once they penetrate cell membranes. When she spilled the poisonous droplet in her lab, she thought nothing of it she was wearing latex gloves. What she didn't know killed her.

The dimethylmercury was volatile enough to penetrate the glove. Five months later Wetterhahn began stumbling into doors and slurring words. After three weeks in a hospital, she slipped into a coma.

"I went to see her, but it wasn't the kind of coma I'd expected," recalled Diane Stearns, one of her postdoctoral students, now a professor of chemistry herself. "She was thrashing about. Her husband saw tears rolling down her face. I asked if she was in pain. The doctors said it didn't appear that her brain could even register pain."

Karen Wetterhahn died five months later. She was 48 years old, a wife and mother of two. The mercury had devoured her brain cells "like termites eating away for months," one of her doctors said. How could such a brilliant, meticulous, worldclass toxicologist come to such an end?

"Only lion tamers are killed by lions," said Kent Sugdan, one of her postdoctoral fellows.

Poison is a stealth killer, effective in minuscule amounts, often undetectable. It's the treachery in the arsenictainted glass of wine. The fatal attraction: Snow White's poison apple, the deathdefying art of the snake handler, the Japanese roulette practiced by those who eat fugu. Without poison, comic book superheroes and villains in plays and movies would be considerably duller. Spiderman exists by the grace of a radioactive spider bite. The rise of the Teenage Mutant Ninja Turtles can be traced to their fall (as pet turtles) into a sewer along with a container of toxic materials. Laertes used a poison-dipped sword to kill Hamlet, and Claude Rains's nasty mother kept sneaking poison drops into Ingrid Bergman's drinks in the Hitchcock thriller Notorious.

You might say that a toxicologist studies substances that lead to death. But toxicology is also about life. What can kill, can cure. Said Paracelsus, a 16th-century German-Swiss physician and alchemist: "All substances are poisons there is none which is not a poison. The right dose differentiates a poison and a remedy." Poison is in the dose. Toxicology and pharmacology are intertwined, inseparable, a Jekyll-Hyde duality. A serpent coiled around a staff symbolizes Asclepius, the Greek god of medicine.

Consider arsenic, the poison of kings and king of poisons. Arsenic exploits certain pathways in our cells, binds to proteins, and creates molecular havoc. Small amounts taken over a long stretch produce weakness, confusion, paralysis. Take less than a tenth of an ounce (2.83 grams) at once, and the classic signs of acute arsenic poisoning ensue: nausea, vomiting, diarrhea, low blood pressure, then death.

Because it is colorless, tasteless, and odorless, arsenic was the poison of choice for the Borgias, the Italian Renaissance family skilled at artful murder, as well as for Hieronyma Spara, a 17th-century Roman entrepreneur who ran a school that taught wealthy young wives how to dispatch their husbands and become wealthy young widows. Arsenic, the poudre de succession, powder of succession, helped ambitious princes secure thrones. Fed in small amounts to a wet nurse, the poison could be expressed in breast milk and kill infant rivals.

From death to life: In the fifth century B.C., Hippocrates used arsenic to treat ulcers. It became an ingredient in Fowler's solution, created in 1786 and used for more than 150 years to treat everything from asthma to cancer. In 1910 an arsenic compound became the first effective remedy for syphilis (later to be replaced by penicillin). Arsenic derivatives are still used to treat African sleeping sickness. In 1890 William Osier, founder of modern medical education, pronounced arsenic the best drug for leukemia, and today it remains an effective chemotherapy agent for acute forms of the disease.

So is arsenic a poison or a drug?

"It's both," says Joshua Hamilton, professor of toxicology and pharmacology at Dartmouth. "It depends: Are you talking to a Borgia, or are you talking to a physician?"

Poisons surround us. It's not just too much of a bad thing like arsenic that can cause trouble, it's too much of nearly anything. Too much vitamin A, hypervitaminosis A, can cause liver damage. Too much vitamin D can damage the kidneys. Too much water can result in hyponatremia, a dilution of the blood's salt content, which disrupts brain, heart, and muscle function.

Even oxygen has a sinister side. "Oxygen is the ultimate toxin," says Michael Trush, a toxicologist at Johns Hopkins Bloomberg School of Public Health. Oxygen combines with food to produce energy, but our bodies also produce oxygen radicals—atoms with an extra electron that damage biomolecules, DNA, proteins, and lipids. "We are oxidizing all the time," says Trush. "The biochemical price of breathing is aging." Which is to say, we rust.

As if everyday poisons aren't enough to angst over, there are nature's more exotic hazards. It's a jungle out there. There are 1,200 kinds of poisonous marine organisms, 700 poisonous fish, 400 venomous snakes, 60 ticks, 75 scorpions, 200 spiders, 750 poisons in more than 1,000 plant species, and several birds whose feathers are toxic when touched or ingested.

Given the treachery of the world, why don't more of us die of poisoning? Because our bodies are designed to protect us from both natural and man-made toxins. The first line of defense, skin, is made of keratin—so waterproof, tough, and tightly woven that only the smallest and most fat-soluble molecules can get through. Our senses warn us of noxious substances if they fail there is vomiting as backup. Finally, there is the liver, which turns fat-soluble poisons into watersoluble wastes that can be flushed out through our kidneys. The balance tilts over to toxicity only when we step over the threshold of dosage.

Mike Gallo, a toxicologist, knows the principle of threshold from the inside out. Literally. Gallo, a hyper-caffeinated personality wrapped in a wiry frame, is an associate director at the Cancer Institute of New Jersey in New Brunswick. In February 2004, at 64, he was diagnosed with non-Hodgkin's lymphoma. Two weeks later he became both toxicologist and patient at the cancer institute. His oncologist put him on a four-month intravenous diet of toxins, also known as chemotherapy, and he began treatment in a clinic four floors down from his office.

The ingredients of his cocktail included cytoxan, adriamycin, vincristine, prednisone, and Retuxan—toxic enough to cause side effects ranging from vomiting, diarrhea, and weight loss, to liver, heart, and bladder damage, to death from overwhelming infection due to a depressed immune system. In addition, as Gallo will cheerfully tell you, "Almost all cancer drugs are carcinogenic in their own right."

On the other hand, he says, "The moment they stuck the needle in my vein, I felt relief. I thought, They got the son of a bitch."

Gallo was lucky. His luxuriant mop of red hair fell out, and he took on the alien look of chemotherapy. But fatigue and the typical drop in blood-cell count aside, he continued working through the treatment.

"I did just fine," he says, "but in the room right next to me is the same person, the same age, the same physique, and he's getting the stuffing kicked out of him. Why? My drug-metabolizing enzymes must be slightly different from his."

It's these pieces of toxicology—the matter of difference, the question of how much or how little, the wavering line between killing and curing—that Gallo loves so much as a scientist. They are the heart of toxicology and thus of poison. "Toxicology gives you the chance to understand biology," he says.

Toxicology also saved his life. Six months and thousands of milligrams of toxic drugs later, Gallo's doctor gave him the all-clear. The lymphoma is in remission.

The tale of two toxicologists ends tragically for one, happily for the other. Karen Wetterhahn lost her life to poison. Michael Gallo owes his life to it. "I dodged a lethal bullet, thanks to a series of well-placed bullets," Gallo says. "I could have been a dead man. Thank God for toxicity."

The Curious Case of Napoleon B.

It's a game of Clue and historical whodunit all in one. The victim, Napoleon Bonaparte, died on May 5, 1821, on St. Helena, in exile after his defeat at Waterloo. An autopsy performed the next morning revealed perforation of the stomach due to an ulcer, possibly cancerous. The real cause of death? In dispute ever since. Some theories:

Murdered by arsenic poisoning, according to Ben Weider, founder of the International Napoleonic Society and head of a huge Canada-based body-building empire. Weider has relentlessly sought the cause of Napoleon's death for more than four decades and has poured considerable resources into the quest. In his view, Napoleon was poisoned by the British and by French royalists, who wanted him out of the way once and for all. Weider offers as the centerpiece of his hypothesis the hair analysis done by Pascal Kintz, a French lexicologist at the Legal Medicine Institute of Strasbourg. Kintz subjected samples of Napoleon's hair to a sophisticated technique known as nanosecondary ion mass spectrometry, which confirmed the longterm presence of arsenic. Kintz steps back from saying how or why the arsenic was there, but Weider is convinced that "the poisoning of Napoleon was planned and deliberate. Anything else is hogwash."

Poisoned by his wallpaper, theorizes David Jones, an immunologist at the University of Newcastle in England. The wallpaper at Longwood House, where Napoleon lived his last years, was painted with Scheele's green, an arsenic compound called copper arsenide. When attacked by certain molds, possibly present in the damp environment of St. Helena, arsenic would have been released into the air. In the late 1950s Clare Boothe Luce, the American ambassador to Italy, was diagnosed with arsenic poisoning caused by paint chips falling from the stucco roses on her bedroom ceiling.

Killed by his doctors, says Steven Karch, a cardiac pathologist in Berkeley, California. Napoleon's doctors gave him large doses of purgatives including tarter emetic and, the day before his death, a massive dose of mercurous chloride, called calomel. The medications threw Napoleon's electrolytes into total disarray, Karch says, disrupting his heartbeat and resulting in cardiac arrest. In pathologist terms, the immediate cause of Napoleon's death was cardiac arrhythmia precipitated by medical negligence and compounded by chronic exposure to arsenic.

Cancer and ulcers as reported in the autopsy, says Jean Tulard, the preeminent Napoleon historian in France. Tulard remains unconvinced by Kintz's hair analysis. In his estimation the provenance of the hair whether it really belonged to Napoleon or not—is one of many problems standing in the way of definitive proof. "There are more samples of Napoleon's hair than relics of the Cross," he scoffs. Above all, Tulard discounts the poisoning theory on the grounds that no one has yet found anything linking Hudson Lowe, the British governor-general of St. Helena—or anyone else for that matter—to any plot against Napoleon's life. "A bogus discussion," he says, "even if it is important to know how he died."

"One of my ancestors did it," says Francois de CandéMontholon with a whiff of pride. ("I'm an aristocrat. Aristocrats don't like revolution, and Napoleon made revolution.")

Candé-Montholon's great-great-great-greatgrandfather, the Count of Montholon, was stationed with Napoleon on St. Helena. Napoleon had an affair—and fathered a child—with the count's wife. The count, it is observed, had charge of Napoleon's wine cellar and food. Could he, motivated by revenge, have poisoned the wine?

"Everyone is right, and no one is right," says Paul Fornes, a forensic pathologist at the Hospital Georges Pompidou in Paris. Fornes has reviewed the 1821 autopsy report and other historical records and concludes: "Napoleon may have died with cancer, but he didn't die of cancer." Likewise he says that although the hair analysis indicates the presence of arsenic, no one can say if he was intentionally given the arsenic (or if it killed him). In Fornes's opinion the accusation of murder by poisoning would never fly in a court of law.

Believe what you will. "We have left the world of history and science behind," says Jean-François Lemaire, a doctor and French historian, disdaining the circus (press conferences! newspaper stories!) surrounding the debate. "We are now in the world of entertainment." Or perhaps, as the French would say, it's a case of couper les cheveux en quatre—splitting hairs.

One bad move and you're snakebit!

During a one-man wildlife survey on a deserted Florida barrier island, herpetologist Bruce Means finds his favorite venomous reptile.*

He knows better, but tries to capture the rattler with a stick…

Defending itself, the snake strikes!

It's only a pinprick on his finger, but Bruce knows the venom will start working within seconds.

Tissues break down as enzymes in the venom attack.

As toxins wreak havoc, Bruce crawls to find help before it's too late.

Blood and other fluids begin to leak into his tissues. His blood is losing its ability to clot. Will he die?

Bruse managed to reach a hospital—and survived, but the eastern diamond-back still claims an occasional life. Venom strength varies depending on the snake's age, when it last ate, the time of day the strike occurs, how deeply the fangs penetrate, and how much venom is injected.

Circulatory failure, shock, massive tissue necrosis, and internal and external blading lead to death. Medical help is the key, but some wait too long before seeking treatment. Others, often children, are just not robust enough to withstand the poison's lethal effect.

Concerto in b for Botox & Piano

"I was lost," Leon Fleisher says, and 40 years later you can still feel the suffocating despair. One of the world's premier concert pianists, Fleisher was talking about the aftermath of a day in 1965 when the career so carefully nurtured (his first public recital at 8 a performance with the New York Philharmonic in Carnegie Hall at 16) unexpectedly ended.

Fleisher, a man with a spirit as expansive as a Beethoven symphony, sits in the music room of his Baltimore home. Twin Steinway grands nest together on one there are photographs of a young, gangly Leonard Bernstein and of George Szell, the legendary maestro of the Cleveland Orchestra ("looking cold as ever," Fleisher notes). The conversation drifts to the day in Cleveland's Severance Hall when Szell rehearsed Fleisher and the orchestra in final preparation for a tour of the Soviet Union. "It was the height of the Cold War. We were going to show the Russians what music was all about," Fleisher recalls. "I had noticed the fourth and fifth fingers on my right hand curling under involuntarily. I figured, Wow, I better work harder. I did. It got worse. George noticed too."

When rehearsal ended, Szell called Fleisher to his study. "I don't think you should come on tour," he said. That was it. Fleisher was 37. His life had evaporated.

There were doctors: orthopedists, neurologists, a hand surgeon, psychiatrists. There were injections, x-rays, medications, acupuncture, aromatherapy. All failed. All useless. "It was as if my hand had been taken over by aliens," he says. "It was not under my control."

A career ruined. A marriage wrecked. Thoughts, even, of suicide.

"Finally I realized my connection to music was stronger than just as a two-handed piano player. I started conducting, playing the left-handed repertory, and teaching at the Peabody Conservatory." Yet the pain of the missing piece of his life persisted. "I taught and conducted and every bloody day I tested this hand." He lifts the offending hand and demonstrates how the fingers curled under like claws.

There was, it should be noted, a brief respite in 1981 when the condition seemed to improve. Fleisher played at the opening of the Meyerhoff Hall in Baltimore. "I managed to get through," he recalls, "but just barely. Afterward I broke down backstage. A grown man weeping. "

After decades a diagnosis emerged. Fleisher was afflicted with focal dystonia, a misfiring of the brain that causes muscles to contract into abnormal, and sometimes painful, positions. The disorder often strikes those who depend on small motor skills: musicians, writers, surgeons. At last relief seemed possible. He was referred to a clinical trial at the National Institutes of Health, where botulinum toxin was being tested as a remedy for the disabling contractions.

Botulinum toxin is produced from the bacterium Clostridium botulinum, one of the most poisonous substances known. A gram of botulinum toxin, if dispersed and ingested, could kill 20 million people. The toxin produces a protein that blocks the release of acetylcholine, a transmitter that tells a muscle to contract. In extremely dilute form the poison, delivered in the drug Botox, has proved effective and safe in medical applications ranging from the softening of wrinkles, to the relief of migraines, to a cure for crossed eyes, to a treatment for the spastic contractions of multiple sclerosis and cerebral palsy.

Botulinum toxin relieves symptoms without curing the condition, so Fleisher receives an injection every six months or so. But the six-month miracle is a miracle no less.

"I have had eight, maybe nine lives," Fleisher says. For each there is cause to celebrate, but maybe most of all for the ninth. He is performing and touring again, and recently released his first two-handed recording in 40 years.

Artur Schnabel, Fleisher's mentor, whose teacher's teacher was Beethoven himself, once said that life is about ascendancy. The only thing that grows down is potatoes, he told his protégé. A conductor beats up. A ballet dancer lifts up. We grow up and outward. "Play upward," Fleisher urges his students.

After 40 years, Fleisher's own life has turned upward as well.

Rye infected with ergot, a toxic fungus, has caused devastating epidemics through history. Symptoms include tremors and hallucinations the hysteria of those accused of witchcraft in the 17th century may have been ergot poisoning.

Spies were sometimes issued lethal pills hidden in objects like eyeglasses to use if captured. "The KGB grabbed spies by the throat so they couldn't swallow," says Peter Earnest of the International Spy Museum in Washington, D.C.

A popcorn cat poisoned several New England children in 1955, when levels of orange food coloring reached toxic levels due to poor manufacturing controls. Victims recovered, and the manufacturer recalled the other cats.

The National Cancer Institute evaluates marine-animal toxins for potential cancer drugs. Animals with no armor and limited mobility rely on poison for defense. NCI scientist David Newman calls it "animal chemical warfare."

Georgi Markov, a Bulgarian dissident, was assassinated in London in 1978 when a man approached and jabbed him with an umbrella modified to fire a pellet with ricin, a deadly toxin. This replica is cut away to show the firing mechanism.

In 1971 a man in Bedford, New York, died of botulinum poisoning after eating vichyssoise made by the Bon Vivant Company. Over a million cans of possibly under–:processed soup were recalled. The company filed for bankruptcy.

A Delicacy to Die For

Meet the fugu, aka Takifugu rubripes, a fish with the thick-lipped, thuggish face of a Chicago gangster. Fugu, or puffer fish, as it is commonly known, is a delicacy in Japan. It can also be deadly. Those who eat the liver, ovaries, gonads, intestines, or skin swallow tetrodotoxin, a powerful neurotoxin that jams the flow of sodium ions into nerve cells and stops nerve impulses dead in their tracks. They run the risk of suffering the fate of the famous Kabuki actor Mitsugoro Bando, who in 1975 spent a night feasting on fugu liver because he enjoyed the pleasant tingling it created on his tongue and lips. The tingling was followed by paralysis of his arms and legs, difficulty breathing, then, eight hours later—death. There is no known antidote.

Fortunately, these days the making of a fugu chef is a carefully controlled and licensed enterprise. Aspiring chefs who would spend their days in the kitchen skinning and shaving the fugu into tissue-thin slices for sashimi (at $500 a plate) must take an exam: 20 minutes to dissect the fish into edible and inedible pieces, label the parts with plastic tags (red for toxic, black for edible), and prepare an artful arrangement. Of the 900 hopefuls who took last year's exam, 63 percent passed.

The source of the fugu's poison is a subject of debate. Tamao Noguchi, a researcher at Nagasaki University, believes the secret lies in the fugu's diet. Puffer fish, he explains, ingest toxins from small organisms—mollusks, worms, or shellfish—that have in turn ingested a toxic bacterium known as vibrio. In experiments, Noguchi has raised fugu in cages, controlled their diet, and produced toxin-free fish.

He hopes his research will result in the state-sanctioned sale of fugu liver. "A great delicacy once you eat, you cannot stop," he says. Japan has forbidden the sale of fugu liver since 1983 before the ban, deaths of those who overindulged in the liver, or ate it by mistake, numbered in the hundreds.

If Noguchi succeeds in his efforts, gourmands may have cause to cheer, though the fish itself, he speculates, may have cause to mourn. "After all," he says, "a fugu without its poison is like a samurai without his sword."

Kendo Matsumura, a research biologist at the Yamaguchi Prefectural Research Institute of Public Health, discounts Noguchi's deadly diet theory. He says the fugu's toxicity comes from poison glands beneath its skin. Some fugu are poisonous, he says, some aren't, but even experts can't tell which is which.

Place your bets. Matsumura has never eaten fugu. "I am not a gambling man," he says. However, Noguchi considers it the ne plus ultra of fine dining.

When it comes to fugu, one man's poisson is another man's poison.

In the Morgue With Al and Marcella

Marcelle Fierro is chief medical examiner of the Commonwealth of Virginia and a professor in the Department of Legal Medicine at Virginia Commonwealth University School of Medicine in Richmond. She oversees the medical investigation of all violent, suspicious, and unnatural deaths in Virginia, and she inspired the character Kay Scarpetta in Patricia Cornwell's crime novels. Alphonse Poklis is director of toxicology and professor of pathology, chemistry, forensics, pharmacology, and toxicology at VCU. He works with Fierro to analyze medical evidence in homicide cases and testifies as an expert in court.

When does the red flag go up? How do you know you're dealing with a murder by poison?

MF: There are a couple of presentations. If someone takes a huge overdose of something toxic, you expect a classic range of symptoms even a first-year resident can pick up on. Chronic poisonings—when toxins are fed slowly, continuously—are easier to misdiagnose. Antifreeze in the Gatorade was a recent case. A common warning sign is when the clinical history is florid. For example, lots of trips to the internist for weird symptoms or stomach pains. The victim doesn't feel well it's diffuse, nonspecific. Of course over time classic elements of poisoning may present: He doesn't eat, he's losing weight, he's sounding more teched each day. It looks like natural disease, but isn't.

At what point do you get called in?

MF: We see any death that is sudden, unexpected, violent, or where there is allegation of foul play. If we have the body before it's in the ground, we deal with it. But often it takes time for an allegation to be made or for someone to believe it. Perhaps a family member has a motive: there's dissension about property, inheritance, a new wife, a child not getting a fair shake. Those things set a chain of events into motion. The body has to be exhumed.

Then what? How do you proceed?

MF: I take umpteen tissue samples at autopsy: heart, liver, lungs, brain, spleen, hair, nails. Blood tells you what was going on in the body at the time of death. Vitreous humor from the eye is great. It's clean. No fermentation or contamination from bacteria. Al and I work together. What poisons are candidates? What best to collect? You have to have a strategy. We'd want to know what poison the defendant would have access to. If it's a farmer, we look for agricultural things like pesticides or herbicides. We need to have an idea of where we are going. We can easily run out of tissue and blood samples before we run out of tests to do.

So the technology you use to detect poisons in a corpse must be pretty sophisticated?

AP: Very. I call it the vanishing zero. In the 1960s it took 25 milliliters of blood to detect morphine. Today we can use one milliliter to do the same work. In terms of sensitivity, we've gone from micrograms to nanograms, which is parts per billion, to parts per trillion with mass spectrometry. You can find anything if you do the research. Of course some substances are more apparent. You can smell cyanide the minute you open a body at autopsy. Cyanide works fast—like in movies where the captured spy bites on the capsule and dies. It's a chemical suffocation cyanide hits the mitochondria in the cells, and every cell is deprived of oxygen. You die quickly, dramatically, violently.

Is there a personality profile specific to poisoners?

AP: The poisoner tries to cover up what he does, as opposed to somebody who shoots, strangles, or rapes you. A forensic psychologist I know calls poisoners custodial killers. Often you are dealing with a family situation. It happens over a period of months or a year. The perpetrator is taking care of the victim, watching him die. Poison is the weapon of controlling, sneaky people with no conscience, no sorrow, no remorse. They are scary, manipulative if you weren't convinced by the evidence, you wouldn't believe they could do such a thing.

MF: Al sees the poisoner as a controller. I see the poisoner as a smooth psychopath who could lie to Christ on the Cross, and you would believe him. I only know of two who pled guilty.

A case that sticks in your mind?

MF: There was this fellow at the University of Virginia hospital. Kept getting admitted for weird gastrointestinal complaints. The doctors were twisting themselves inside out to figure it out. He'd get better his wife would come in to see him in the hospital and bring him banana pudding. Someone finally ordered a heavy metals [toxicity tests] on him, but he was discharged before the results came back—off the charts for arsenic. By the time someone saw the labs it was too late. We called the wife Banana Pudding Lily.

How many cases of suspected homicidal poisonings do you evaluate in the course of a year?

AP: Frankly, relatively few. It's not in the American character. If you are going to kill someone and you are a true American, you shoot them. A real man doesn't sneak around. In our culture everything is solved in 30 minutes, so you aren't going to plan, go someplace to get poison, and figure out How am I going to give it? In our culture, we act directly.

You're the expert. If you had to design the perfect poison for murder, what would it be made of?

AP: I could think of a few things, but I'm not going to share them.

When you think about it, not much has changed in 500 years. Spies, assassinations, covert contracts, secret payoffs—it's all part of the everyday business of running a country.

In Renaissance Italy "poison was the solution to delicate political problems," says Paolo Preto, a professor of modern history at the University of Padua. So it should be no surprise that poisoning was as much an art as painting, architecture, or sculpture. A touch of arsenic, hemlock, or hellebore added to the wine was discreet, nearly undetectable (autopsies were rare at the time), and considerably less messy than using a knife or gun.

The Borgias—Alexander VI and his son Cesare—specialized in faith-based poisonings. As pope, Alexander appointed wealthy men as bishops and cardinals, allowed them to increase their holdings, then invited them to dinner. The house wine, dry, with overtones of arsenic, neatly dispatched the guests, whose wealth, by church law, then reverted to their host. English essayist Max Beerbohm wrote: "The Borgias selected and laid down rare poisons in their cellars with as much thought as they gave to their vintage wines. Though you would often in the 15th century have heard the snobbish Roman say . 'I am dining with the Borgias tonight,' no Roman ever was able to say 'I dined last night with the Borgias.' "

But the capital of conspiracy in Italy was Venice, where the architects of evil were the Council of Ten, a special tribunal created to avert plots and crimes against the state. To accomplish poisoning, the council would contract with an assassin, usually from another city. The deed, when done, was paid for through an intermediary. Funds were readily available for such matters, and the council kept two accountings: one for public dealings and one for those of a private nature.

The council's cloak-and-poison-dagger proceedings were recorded officially (opposite, bottom) in a thin volume marked Secreto Secretissima ("top top secret"). Those present swore twice on the Bible to keep the meetings secret, forbidden even to admit they took place. Today the ledger sits in a soaring arched space in the state archives in Venice.

Consider the scheme proposed in its pages by a doctor to a Venetian general fighting against the Turks in Dalmatia. He offered to cut the infected glands off bubonic plague victims and create a toxic potion to be spread on woolen caps, which could then be sold cheaply behind enemy lines to the Turks. Presumably, plague and buyer's remorse would result. The plot was enthusiastically endorsed by the general until someone gently reminded him that because so many Venetian troops were stationed behind the lines in Dalmatia, his soldiers could be infected too and perish along with the enemy.

Last year poison, dioxin to be exact, was the lead player in the drama of Ukrainian President Viktor Yushchenko, victim of an attempt to remove him from the political scene. In the United States such covert plots became the subject of congressional investigations after the early 1960s, when the elimination of Cuban dictator Fidel Castro was a top CIA priority. Mobsters enlisted in the planning advised against a hail of machine-gun fire in favor of a more subtle approach: a bottle of botulinum-laced pills. Other plans, considered then rejected, included the delivery of a box of botulinum-soaked cigars, contaminating Castro's scuba breathing apparatus with tubercle bacilli, or sprinkling his shoes with thallium salts in hopes that hair loss, one of the common side effects of thallium absorption, would make his beard fall off.

Though the recurring narrative of poisoning plots might lead one to despair for the human race, Paolo Preto, who spent eight years researching dark dealings in the Venetian state, takes a pragmatic approach. "History is made up of bad acts," he says.

Zyklon B and the Camp of Death

In the summer of 1941 Himmler informed me of the following: "The Fuhrer has ordered the final solution of the Jewish question. We, the SS, are to carry out the order. The existing extermination sites in the east cannot cope with the large scale of the planned operation. I have therefore designated Auschwitz for this purpose. "

—Rudolf Hoss, Commandant, Auschwitz

On September 3, 1941, at Auschwitz, a concentration camp in Poland, Nazi security guards forced 600 Soviet prisoners of war and 250 ill inmates into a locked room. They poured pellets of Zyklon B, a crystallized form of hydrogen cyanide normally used as an insecticide, through a vent and watched.

Previous mass killings had been carried out by shooting squads or by pumping exhaust fumes into sealed vans. The former method, however, was too slow and created too much of a public spectacle the latter was unreliable and required special equipment.

The Zyklon B pellets proved effective, efficient, and infallible. Exposed to air, they turned to gas, which killed all occupants of the room in 20 minutes. After the experiment the Nazis built four larger, permanent gas chambers and crematories in Birkenau, a sub-camp of Auschwitz. The key to the final solution, Adolf Hitler's plan to exterminate the Jews of Europe, was Zyklon B.

Stefan Polchlopek, who grew up and still lives in Krynica, Poland, was arrested by the Gestapo on December 28, 1942. He was 26 years old, a law-school graduate, and an active member of the resistance. When he was arrested, someone told his mother, who ran to the railway tracks and managed to wave goodbye to her son as he was hauled away.

Polchlopek was taken to a collection point, then put on another train for Birkenau. The car was a solid, stifling mass of prisoners. When the train stopped, he recalls, "the doors opened we heard shots, howling of dogs, and screams. Searchlights glared in our faces. They told us to jump off, and we fell to an indescribable hell."

In the summer of 1943, Polchlopek worked in a labor crew assigned to extend the railway line from a depot outside the camp right up to the gas chambers. Transports from throughout Europe were arriving two or three a day. Jews, Gypsies, political dissidents like Polchlopek, homosexuals—anyone considered undesirable by the Nazis—were unloaded from railcars and either taken to the gas chambers or consigned to slave labor.

One day, an SS officer approached Polchlopek and three other prisoners working on the line and ordered them into the undressing room, the chamber in front of the room where the gassings took place. He made them collect the clothes and belongings of those who had been killed.

"I saw the undressing room and the gas chamber," Polchlopek, now 89, says. "I remember the showerheads. I remember the clothes, shoes, the personal possessions left in pockets. We had to gather up the clothes and load them into trucks. The belongings would go to warehouses where they would be sorted. The smell of burned corpses was in the air dark smoke poured out of the chimneys. We realized we should flee. Witnesses were killed. We could be next." And so they fled. They ran back to the barracks.

"Everyone knew about the chambers. Once I saw two trucks crowded with women. They knew where they were going. One woman was praying. One was cursing. All were screaming. They were followed by two trucks filled with firewood. The women were killed with Zyklon B. The naked corpses were taken out, thrown into pits, and burned."

At the height of operations, nearly 8,000 people were gassed each day at Auschwitz Birkenau. By November 1944, more than one million men, women, and children had died. "Those of us who survived Birkenau are assured a place in heaven," Polchlopeksays. "We have already experienced hell."

History is one long arms race—from sticks and stones to nuclear weapons. According to Adrienne Mayor, a classical folklorist, the Greek superhero Hercules invented the first biological weapon described in Western literature, and it's been downhill ever since.

Hercules slew Hydra, a mythical manyheaded serpent, then dipped his arrows in the venom to ensure their lethality. The legacy endures in the word "toxic," from toxikon, Greek for poison arrow.

In A.D. 199 the Romans attacked Hatra, a city in today's Iraq. Citizens retaliated by lobbing clay pots filled with deadly scorpions over the walls. Hannibal had devised a similar strategy 400 years earlier. His sailors catapulted pots full of venomous snakes onto the decks of the opposing fleet. In Neolithic times, some scholars suggest, a plugged beehive tossed into a cave may have flushed an enemy out.

Other biological weapons in history's armory of terror include the smallpox-infected blankets the British sent to American Indians during the French and Indian Wars the animal carcasses thrown by Confederate forces into wells during the U.S. Civil War the sharp bamboo stakes smeared with feces by the Vietcong.

Today's toxic weaponry includes anthrax letters, which killed five people in the U.S. in 2001, and sarin, which killed 12 when members of a cult released the poison gas in a Tokyo subway in 1995. Such grim reality prompts defensive maneuvers like the exercise held by the U.S. Capitol Police last November in Washington, D.C.—a rehearsal for a scenario in which a poisonous substance is released in the Capitol Building.

What goes around comes around. Along with enemies, Hercules' poison arrows killed old friends and innocent bystanders. Ultimately, the law of unintended consequences claimed Hercules too. Tricked by one of his victims, Hercules made the fatal mistake of putting on a robe dipped in Hydra venom. The mythmakers specialized in irony.

Before Hercules died, he passed his poison arrows on to Philoctetes, a gifted archer, who killed many soldiers in the Trojan War. Death begets death, but—at least this time—reason prevailed. Philoctetes decided not to pass his deadly arrows on to a younger generation. He founded a temple and left the poison arrows behind. In a gesture of hope, he dedicated them to Apollo, god of healing.

The Monk Who Embalmed Himself

To live according to the precepts of a stringent religion can be difficult. To die by the precepts of a religion is another thing altogether.

In the shadow of Mount Yudono in Japan's Yamagata prefecture, the landscape lifts into a corrugated carpet of evergreen. This is the land of mummified priests, those who have, in a purification rite known as the "thousand day training," deliberately poisoned—and at the same time preserved—themselves in compliance with the teachings of a ninth-century monk named Kukai, follower of an esoteric sect of Buddhism called Shingon.

"It is the principle of 'I suffer so that you might live,'" explains Yugaku Endo, the chief priest (95th in a line) of the Dainichibo temple, home to one of 27 such mummified priests in Japan.

For 76 years, Yugaku Endo recounts, the priest known as Daijuku Bosatsu Shinnyokai Shonin lived in austerity. He ate nothing except berries, bark, and nuts. He spent his days and nights climbing in the mountains, through the heat of summer and snows of winter.

Finally he sensed his days were coming to an end and ate nothing. He feasted on the idea of starvation and self-sacrifice. He grew thin, then thinner. He sipped tea made from the toxic sap of the urushi tree, used to make lacquer. Near the end he drank only from hotspring waters that, unbeknownst to him, contained high levels of arsenic.

The urushi sap, a purgative, induced vomiting and urination, desiccating the priest's body. Arsenic, a preservative, killed bacteria that would cause decay. Shriveled, emaciated, he withered away. When he died in 1783 at 96, he was buried in a mound of earth and stones. Three years later, when exhumed, his skin looked as if lacquered onto a skeleton. He had become a sokushinbutsu, instant Buddha.

Often we die as we have lived. The brave die bravely. Cowards die cowardly.

Through history poison has served such ends. Socrates, sentenced to death by an Athenian jury in 399 B.C., on charges of corrupting the city's youth and interfering with its religion, accepted the judgment with grace, drank hemlock, and died in the company of his friends. Defiant Cleopatra, preferring death to being paraded as a spoil of war by the conquering Roman Octavian, opted, it is said, for the fatal bite of an asp. Adolf Hitler, confronted with defeat, chose cyanide (after first dosing his Alsatian to test the toxin's efficiency).

Today Daijuku Bosatsu Shinnyokai Shonin resides in a glass case in the Dainichibo temple, wrapped in red and gold robes. He sits in a pose of meditation—a man of holy belief shriveled by time, the tradition of his religion, and the deliberate ingestion of poison, intent on serving others through the suffering and obliteration of the self.

Chuck Chuck Kristensen has 70,000 mouths to feed and didn't get to bed until 6 a.m., so he is entitled to doze off in the middle of an interview. Kristensen's dependents are spiders: 20,000 black widow babies, thousands of brown recluses and tarantulas, and a few scorpion species besides. The horde constitutes the holdings of Kristensen's company, SpiderPharm. It takes 16 hours to get the spider cafeteria in order each day. No sooner is one meal finished then it's time for the next. The round-the-clock menu includes four sizes of houseflies and fruit flies, wax worms, and, for the tarantulas, an occasional mouse.

Kristensen raises spiders for their venom, which he extracts into tiny vials. It is powerful stuff. A black widow bite can cause severe pain and muscle spasms in a recipient. Brown recluse venom degrades tissue and produces a gangrene-like wound. Funnel spider venom leads to trembling, increased blood pressure, and vomiting. Other spider venoms punch holes in cell membranes, leading to cell death.

Kristensen sends his vials of spider venom to scientists around the world because poison, the death dealer, teaches about life as well. Roderick MacKinnon, winner of the 2003 Nobel Prize in chemistry, used tarantula and scorpion venom to help decipher the structure and function of potassium ion channels in cells.

Ion channels are conduits, like gates, that control the transmission of electrical impulses within cells. Because their opening and shutting in the cell's membrane controls the entry of potassium, calcium, sodium, or chloride ions, the channels and their receptors act as on-off switches that allow a thought, a heartbeat, a breath, the lift of an eyebrow to proceed—or not.

Tarantula toxins can stimulate receptors to hold a gate open in the neurological equivalent of an electrical surge, or slam it shut in the equivalent of a power failure. A busted gate provokes conditions ranging from numbing to outright paralysis on one end to muscle contractions or convulsions on the other. The same malfunction can provoke high blood pressure, cardiac arrhythmia, or epilepsy.

Spider venoms provoke such potent physiological responses that they turn a spider into a virtual Svengali. But why doesn't a spider just knock out its prey and sit down to lunch? In life things are always complicated, Kristensen says. A tree spider may not want a fast knockout: Its meal would curl up and fall out of the tree. Paralysis is the better option. It's the insect equivalent of the surgical strike.

So scientists seek the chemical mastery of the spider. Says Kristensen, "Who controls potassium channels controls the world."

When Your First Bite Might Be Your Last

Among the occupational hazards of being king, tsar, or maharaja, few are so permanently incapacitating as a pinch of arsenic slipped into the soup. For that the royals have long had a remedy: the food taster.

For three generations the family of Mathura Prasad held the post of food taster to the thakur, or lord, of Castle Mandawa in India's Thar desert. "Food was kept under lock and key," he recalls. Before entering the kitchen, "the cook would bathe and change into different clothes. Guards would check his pockets and turban to make sure he wasn't hiding anything. Only then would he be allowed in. When the food was ready, some from each dish would be fed to a dog. Next I would taste, then the guards. The food would go to table under armed escort. Several trusted generals would test it. Finally, the lord and his guest would exchange bits of each dish. Just in case."

Such things are no longer done at Castle Mandawa, now a hotel. But recently, when the vice president of India came to lunch, a food taster sampled the spread. Just in case.

Mithridates, King of Pontus and enemy of Rome, tested poison antidotes on prisoners and nibbled a mix of 54 ingredients to protect himself against poisoning. The Roman emperor Nero commandeered slaves to differentiate between edible and poisonous mushrooms. An armed guard escorted dinner to the table at the court of Louis XIV, and Columbus carried dogs on his second voyage to taste foods his crew had to eat in exchanges of goodwill with natives of newfound cultures.

Medieval rulers experimented with crystal goblets and stones reputed to detect poison on contact. But the tried-and-true means of aftersupper survival was the you-go-first food taster. By tradition, food to be tested before it was served to the ruler was set on a sideboard, or credenza. The Italian word comes from the Latin credential, meaning "confidence."

These days, employment opportunities for tasters are in decline. In England, Buckingham Palace reports there is no formal procedure for food tasting. "The in-house help are fully vetted," a palace spokesman says. The Japanese emperor hasn't used a food taster in years, though President George W. Bush has used Navy mess specialists to handle the job. In the state kitchens of Thailand, humans are factored out altogether. There, in an inspired example of equal opportunity employment, the taste-test heroes of the banquet table, directed by the Ministry of Health, are a legion of white mice.

Effect on the Parasympathetic Nervous System

Our autonomic nervous system—the part of the nervous system that we can&apost control voluntarily𠅌onsists of two divisions.

  • The sympathetic division of the autonomic nervous system prepares our bodies for emergencies. It’s often said to stimulate the 𠇏light or fight” response. It causes the heart to beat faster, the breathing rate to increase, and the pupils to dilate. It also inhibits digestion.
  • The parasympathetic division produces the opposite effects and is sometimes called the “rest and digest” system. It relaxes the body, slows the heartbeat and breathing rate, constricts the pupils, and stimulates digestion.

Atropine interferes with the action of the parasympathetic nervous system because the nerve cells of this system release acetylcholine. Atropine blocks the muscarinic receptors of the system, preventing the acetylcholine from transmitting nerve impulses. Without the action of parasympathetic nerves, the body is unable to counteract sympathetic stimulation and the balance between sympathetic and parasympathetic stimulation is destroyed.

Deadly nightshade must never be used to treat a health problem. It&aposs called "deadly" for a good reason. Atropine must only be used when prescribed by a healthcare professional and must be administered in the correct concentration and quantity.

How do we learn how chemicals affect health?

We don't know all the effects of exposure to every chemical. We learn about the health effects of many chemicals from human exposures and animal studies.

    Human Exposures: Information about human exposures that have occurred at work or by accident is very useful, even though it may be incomplete. For example, if a person has been exposed to more than one substance, it may be hard to find out exactly which substance caused a health effect. Also, some health effects (such as cancer) don't appear until many years after the first exposure, making the cause of the disease hard to determine. Even when the substance that caused the health effect is known, the exact dose that caused the effect may not be.

Sometimes a human population that has been exposed to a toxic substance (usually at work or from an environmental source) is compared with a population that has not been exposed. If the exposed population shows an increase in a certain health effect, that health effect may be related to the chemical exposure. However, these studies often cannot determine the exact cause of a health effect.

The form of causation in health, disease and intervention: biopsychosocial dispositionalism, conserved quantity transfers and dualist mechanistic chains

Causation is important when considering: how an organism maintains health why disease arises in a healthy person and, how one may intervene to change the course of a disease. This paper explores the form of causative relationships in health, disease and intervention, with particular regard to the pathological and biopsychosocial models. Consistent with the philosophical view of dispositionalism, we believe that objects are the fundamental relata of causation. By accepting the broad scope of the biopsychosocial model, we argue that psychological and social constructs be considered objects. We think that this ‘biopsychosocial dispositionalism’ offers the flexibility required to describe causation throughout health, disease and intervention pathways. When constructing mechanistic chains to describe causative pathways, we argue that an object will causally connect with others through actions transfers of energy from one object to another, initiated by the manifestation of one or more dispositional property. Finally, our analysis of causative interactions utilises the concept that a common form of interaction exists between disease and intervention pathways. This common form will always be an object, but the mode of interaction will vary with each disease. We describe how intervention may act through objects being shared between converging mechanistic chains, or through the removal and/or insertion of objects in such chains. We believe that this analysis provides novel insight to the forms of causative transactions that can occur. In addition, we hope that the findings of this analysis represent the first step towards developing a framework for appraising the composition of mechanistic theories.

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Ilya Mechnikov

I am here before you by virtue of paragraph 9 of the Statutes of the Nobel Foundation, which states that “it shall be incumbent on a prize-winner, whenever this is possible, to give a public lecture on a subject connected with the work for which the prize has been awarded, such a lecture to be given within six months of Commemoration Day, in Stockholm”.

I have had the great honour of receiving, together with my excellent friend, Professor Ehrlich, the Nobel Prize for Medicine “for work on immunity”, so that it is on this subject that I shall speak. Since the study of immunity is a chapter in medical theory, and theory is often hard to expound to an audience unequipped with the special notions implied, you see the difficulty that lies before me. Fortunately, the theoretical problem on which I shall enlarge concerns the resistance of the body the disease. Whatever concerns health is of real public interest. I take advantage of this to make my address less arduous for you. I shall moreover use the opportunity to show you the practical value of pure research.

There is no need to be a doctor or a scientist to wonder why the human body is capable of resisting so many harmful agents in the course of everyday life. It is often seen that in households where all members are exposed to the same danger, or again in schools or troops where everyone lives the same life, disease does not strike everyone indifferently. For some individuals who go down at the attack, there are others who have immunity to a greater or lesser extent.

There used to be only a vague answer to the problem of the body’s resistance, remarkable as it is. Since the memorable discoveries of Pasteur and his co-workers who found that immunity could be conferred by means of vaccination with microbes, the question has all at once become vastly clarified. The problem has become open to study by experiment. For Pasteur, who was a chemist, the fact that the undamaged organism does not allow certain morbid agents to spread within it, could be explained simply in terms of the chemistry of the environment. In the same way that plants will not grow on soil that lacks some substance indispensable to their growth, so microbes, these microscopic plants which cause infectious disease, are unable to grow in an organism which does not give them all the substances they need.

This theory is completely logical but contradicted a number of factors to be found in the protected organism. Pasteur and his fellow workers realized this themselves when they found that infectious microbes develop very well in the blood of animals that enjoy complete immunity.

The animal organism is very complex and for this reason it is often hard to explain in simple concepts the phenomena to be observed. To achieve the purpose, a different approach has had to be called for. It has been necessary to look from the point of view of biology, and attempt to simplify research conditions without going beyond the scope of the living organism. This is the idea that has been behind our research. Disease is not the prerogative of man and the domestic animals, so it was quite natural to see if the lower animals, with very simple organizations, showed pathological phenomena, and if so, infection, cure and immunity could be observed among them.

To solve medical problems, comparative pathology had to be called in.

While studying the origin of the digestive organs in the animal world, we were struck by the fact that certain of the organism’s elements which have no part to play in the digestion of food are nevertheless capable of storing foreign bodies. For us, the reason was that these elements had once been part of the digestive system. This question of pure zoology has no further place here, so we will only stress the general outcome of our research in this field, which was that the elements of the organism of man and the animals, gifted with autonomic movements and capable of enveloping foreign bodies are no more than remains from the digestive system of primitive beings.

Certain of the lower animals, transparent enough to be observed alive, clearly show in their midst a host of small cells with moving extensions. In these animals the smallest lesion brings an accumulation of these elements at the point of damage. In small transparent larvae, it can easily be shown that the moving cells, reunited at the damage point do often close over foreign bodies.

Such observations on the one hand confirmed our assumption on the origin of these migrant elements, while on the other they suggested that accumulation round lesions is a sort of natural defence on the part of the organism. Some method had to be found by which this hypothesis could be verified. I was at this time – more than twenty five years ago – in Messina, so I turned to the floating larvae of starfish, which had been found for the first time on Scandinavian shores and called Bipinnaria. Large enough for several operations, they are transparent and can be observed alive under the microscope.

Sharp splinters were introduced into the bodies of these Bipinnaria and the next day I could see a mass of moving cells surrounding the foreign bodies to form a thick cushion layer. The analogy between this phenomenon and what happens when a man has a splinter that causes inflammation and suppuration is extraordinary. The only thing is that in the larva of the starfish, the accumulation of mobile cells round the foreign body is done without any help from the blood vessels or the nervous system, for the simple reason that these animals do not have either the one or the other. It is thus thanks to a sort of spontaneous action that the cells group round the splinter.

The experiment I have just outlined shows the first stage of inflammation in the animal world. Now inflammation as understood in man and the higher animals is a phenomenon that almost always results from the intervention of some pathogenic microbe. So it is held that the afflux of mobile cells towards points of lesion shows the organism’s reaction against foreign bodies in general and against infectious microbes in particular. On this hypothesis, disease would be a fight between the morbid agent, the microbe from outside, and the mobile cells of the organism itself. Cure would come from the victory of the cells and immunity would be the sign of their acting sufficiently to prevent the microbial onslaught.

This deduction, based on the fundamental experiment with the splinter in Bipinnaria, had to be checked by observations and specific experimentation. Luckily for us, it is not only man and the higher animals that are subject to infectious diseases. These diseases existed on the earth long before the appearance of the human race and few are the creatures which escape them.

Therefore, to demonstrate the value of the hypothesis I have mentioned, some higher animal was needed, small and transparent enough to be observed living under the microscope and yet subject to microbial disease.

Several starts were made. It became possible to study the progress of infection in fresh-water animals, commonly known as “water-fleas”. These small crustaceans abound in all kinds of stagnant water and are subject to various diseases. One is caused by a tiny microbe characterized by the production of spores in the shape of needles. Swallowed by the water-fleas or Daphniae, which is the scientific term, these spores readily damage the intestinal wall and penetrate to the body cavity. Once they have insinuated themselves into the organism’s inmost part, the spores cause an accumulation of the mobile cells round them, which correspond to the white corpuscles in human blood. A battle takes place between the two elements. Sometimes the spores succeed in breeding. Microbes are generated that secrete a substance capable of dissolving the mobile cells. Such cases are rare on the whole. Far more often it happens that the mobile cells kill and digest the infectious spores and thus ensure immunity for the organism.

This description is from a living animal and can be observed at each stage under the microscope with such precision as could hardly be bettered.

The results obtained from the larvae of starfish and from disease in water-fleas form the bedrock of the theory that I am here to expound. This theory came under heavy fire from the greatest names in science and there was some doubt that such an attack was to be withstood. The memory of the Bipinnaria and the splinter surrounded by mobile cells and the Daphniae with their blood corpuscles devouring the dangerous spores of the infectious microbe, these gave me hope to fight on. Controlled observations on living organism can not be wrong.

Having established the base of the theory of immunity, it had to be applied to the higher organisms and even to man himself. Conditions were incomparably more complex than in the little transparent creatures, and difficulties arose on all sides. Given the impossibility of submitting a vertebrate, even the smallest such as a new-born mouse, to direct examination by microscope, a more complicated way had to be taken, by combining the results of research on the blood and organs extracted from the organism, and thinking out the interconnection. In such circumstances, the door is wide open to mistakes of all sorts.

The study of various infectious diseases in man and the higher animals showed first that the facts observed corresponded very satisfactorily with the theory based on research on the lower, transparent animals. Whenever the organism enjoys immunity, the introduction of infectious microbes is followed by the accumulation of mobile cells, of white corpuscles of the blood in particular which absorb the microbes and destroy them. The white corpuscles and the other cells capable of doing this have been designated “phagocytes”, i.e. devouring cells, and the whole function that ensures immunity has been given the name of “phagocytosis”.

It has been established as a general rule that in all cases of immunity, natural or acquired, either by preventive vaccination or following an attack of infectious illness, phagocytosis takes place to a marked degree, whereas in fatal or very dangerous diseases, this phenomenon does not exist at all or is attenuated. This rule was demonstrated for the first time on animals immunized against anthrax. When the anthrax bacillus is injected under the skin of sensitive animals, such as the rabbit or the guinea-pig, the microbe is found free in abundant fluid from which the white corpuscles are almost wholly absent. When however the same inoculation is carried out on a rabbit or a guinea-pig that has been previously vaccinated against anthrax, a very different picture results. The bacilli are within a short space of time seized by the white corpuscles which accumulate in quantity at the inoculation point. Once inside the phagocytes, the bacilli die within a comparatively short time. It happens on occasion that only a few hours after the absorption of the bacilli by the white corpuscles, the bacilli are dead.

In time the same rule has been extended to cover a whole host of other infectious diseases. Every time the organism enjoys immunity, the infectious agent falls prey to the phagocytes that gather round the microbes. This general law has even been verified by studying pathogenic microbes, discovered since the law was formulated. With plague, in all cases where the organism is refractory, the plague bacillus is devoured and destroyed by the phagocytes, while in fatal cases of plague the majority of the microbes remain free in the organism’s fluids and multiply without hindrance.

To date we have found no exceptions worthy of note to this rule. It is true Weil of Prague has maintained in several publications that in cases of immunity regarding the cholera microbe in hens, the refractory organism meets the microbial invasion by other means than phagocytes. He bases his case on the impossibility of finding this microbe inside the white corpuscles in animals that are resistant to illness. This exception is not a true one. It is explained by the minute dimensions of the cholera microbe in hens, owing to which it easily eludes the eye of the beholder. Soulima examined this question very thoroughly in my laboratory and he found it to be true that, in accordance with the general law, in animals refractory to the cholera bacillus of hens, it is again the white corpuscles that take hold of the microbe and cause it to disappear within themselves.

Opposers of the phagocyte theory have long taken the view that the white corpuscles and phagocytes in general are only capable of absorbing microbes that have first been killed by the humours of the organism, namely blood plasma and exudative fluids. It would today be hard to find anyone who still maintains this view. Many accurate experiments have shown that the phagocytes surround the infectious microbes while these are quite alive and in a condition where they are capable of bringing fatal infection to the organism that does not enjoy immunity.

The results which I have thus summarized have been achieved after many a long year of research and discussions. Many scientists still kept to the old idea, that the white corpuscles represent an element hostile to health. In serious illness, collections of pus used to be met with. This was thought to consist of white corpuscles only, as the microbes were too small to be detected by the imperfect tools of microscope research. It was supposed that the pus corpuscles themselves might be the source of disease found in the morbid alteration of our cells. When later microbes came to light inside the white corpuscles, it was admitted that the corpuscles, as ill-omened elements in our body, only serve to feed and spread the body’s worst enemies, namely the agents of infection. The destruction of these in cases of immunity was rather attributed to the direct influence of the organisms’s fluids.

The theory of the bactericidal action of the humours was brought in against the phagocyte theory. To the organism enjoying immunity, natural or acquired, was attributed the power of destroying the infectious microbes without any real assistance from the live cells. This affirmation was based on well-known instances, in which blood and blood serum taken from the organism proved able to kill a considerable quantity of infectious microbes. This theory of the humoral immunity met multiple and major contradictions from the outset, yet it was not without ardent support. The discovery of Pfeiffer was of great assistance to the theory, for he demonstrated the destruction of cholera vibrios in the humour of the abdominal cavity in animals immunized against this microbe. This case has become classic. The vibrios do not die within the phagocytes but in the fluid of the peritoneal secretion. Every attempt was made to show that this was not a case of an exception to the rule, but the demonstration of a general law of immunity. But, after years of hard research, it has been conclusively shown that the vast majority of infectious microbes can not be destroyed by the liquids of the organism and that the instance of the vibrios is to be explained by their extreme fragility. It was also maintained that the destruction of the vibrios by the humours took place by means of the bactericidal substances released by the white corpuscles present in the abdominal cavity. In cases where the very microbes had been introduced to regions of the organism where there were no white corpuscles already in existence, then the destruction of the vibrios was done within the phagocytes which came on to the field of battle. Even in the abdominal cavity, the extracellular destruction of the vibrios was easily to be avoided if the white corpuscles were prevented from suffering and thus from spreading their bactericidal substances. This experimental observation was denied by many observers over a period of years. It was however conclusively confirmed some years back by Bail of Prague. It has thus been clearly shown that as long as the white corpuscles are intact, the destruction of vibrios in the organism that has immunity takes place within the phagocytes.

Thorough analysis of the phenomena of immunization, an analysis based on extremely numerous experiments, has shown that phagocytosis is in truth a defence action on the part of the organism against the agents of disease. Several of the former supporters of the exclusively humoral theories of immunity later came round to the cellular theory, with more or less important reserve, however. So various intermediate theories were adduced, according to which the organism, threatened by microbial onrush, brought all its resources into play: phagocytes and humours. For some, the destruction of certain infectious agents in the cases of immunity was by the organism fluids, especially the blood plasma, while other microbes had greater resistance and were only killed within the phagocytes. This eclectic theory was developed in the main by your compatriot, A. Pettersson.

For this defence action, the organism would make use of two classes of bactericidal substances, one of which would be circulating in the blood fluid and flow thence to the exudations formed round the microbes, while the other group would only be found within the phagocytes. The first category would react first and foremost on the cholera vibrio, typhoid bacilli and their congeners, while the other would destroy anthrax bacilli, suppuration microbes and others as well.

Just as there were two diverse bactericidal functions of the organism, so the nature of the substances that destroy the microbes would be diverse. The bactericidal substances of the humours would be of complex nature, consisting of a substance that would prepare the microbes, without damaging them, for the action of the substance that would kill them. Various names were put forward to designate these two substances. Ehrlich gave the name of amboceptor to the preparatory substance and the name of complement to that which destroys the microbes. Not to complicate further matters that are very complicated already, we shall use the terms proposed by our eminent colleague, without sharing his view of the actual part played by the two substances.

Formerly, I mean to say ten years and more ago, certain scientists thought that the bactericidal substance proper, although circulating in the blood fluid, was nevertheless a secretion of the white corpuscles. Of late more and more voices state the contrary to be the case. It is readily admitted that the complement has nothing to do with the corpuscles and has a completely different origin. This view is based on much research carried out with extracts prepared from the white corpuscles taken out of the organism. To this end, exudations that are very rich in these corpuscles are used. They are washed to rid them of liquid parts and then they are killed by subjecting them to cold and letting them macerate in physiological fluid. In the extracts of white corpuscles obtained in this way, no complements are found capable of destroying microbes. This is established, for it has been checked and counterchecked on innumerable occasions. It is not however correct to conclude on this account that the white corpuscles do not produce the complement.

To form an opinion on this much discussed topic, Levaditi and I began to study the bactericidal properties of white corpuscles. First of all we found that these cells, taken from the organism, are indeed capable of absorbing and destroying many microbes. Making use of Deneke vibrios, that resemble the microbes of Asian cholera, we were able to show quite easily their transformation into granules in the interior of the white corpuscles of guinea-pigs. This transformation, which takes place very fast with vibrios impregnated with the amboceptor or preparatory substance, implies their destruction. The white corpuscles must therefore contain in their components a substance which acts just like the complement of the humours. Now let us see how the substance behaves in fluids deprived of this bactericidal substance but having a large quantity of white corpuscles possessing the complement. One has only to keep these elements for twenty hours to discover that at the end of that time they have become completely incapable of transforming the vibrios charged with the amboceptor. The corpuscles have had time to die for the most part and in these circumstances the vibrios remain intact.

We have repeated this experiment several times with the same result, thus showing that the complement in the white corpuscles is a very fragile substance. It is beyond doubt that the long operations of washing, cooling and maceration of the white corpuscles are destructive for the complement, by and large. That is why this method must be rejected in studying the bactericidal substances in white corpuscles.

Do not think that as the action of the complement is only manifest while the white corpuscles are alive, this is purely a vital phenomenon. On the contrary it is most likely that this is a chemical action which alters according to the state of the white corpuscles. Here is an analogous example which will support this view.

The magnificent masses of living matter to be found in certain mushrooms known as “Myxomycetes” are capable, like the white corpuscles, of enveloping foreign bodies and digesting them inside the vacuoles. These are filled with acid juice which favours digestion and whose function is readily demonstrable by giving the living matter some blue litmus particles to absorb, which in a short time turn pink. Well, without killing the living protoplasm, it is enough to bruise it by pressing lightly, and the grains turn blue again. The reason is that the living matter is full of alkaline substance which straightway, at the least shock, penetrates into the juices of the vacuoles and neutralizes the acid in them. This is an example of purely chemical reaction, closely linked to the being and well-being of living matter.

It may be asked why the action of the complement is so fleeting in the white corpuscles, when it lasts much longer in the humours taken from the organism, such as blood serum. We believe the difference to lie in that the white corpuscles, over and above the complement, contain an anti-complement substance as well which prevents the action of the complement, just as the myxomycetes besides the acid juice contain alkaline substances.

Without going into more thorough analysis of this question, we can state that the white corpuscles are microscopic organisms that are more complex than they appear at first sight and that to deal with them in the mass to make extracts is almost as rough a method as squeezing whole animals, say mice or frogs, to find out their digestive powers.

As a result of research which we can do no more than outline to you in summary fashion, we still hold that the complement of the humours comes from the white corpuscles. When the white corpuscles suffer a faint attack, they only release the complement into the fluids in which they are immersed. When however the white corpuscles are subject to more serious lesion, a substance is released which neutralizes the action of the complement. We can quote as evidence to support this opinion that in the immunized organism, where the white corpuscles are intact, vibrios do not undergo the granular transformation in the humours and only take granular form in the interior of the white corpuscles.

Our plea is one of identity, for the complements contained in phagocytes and for those in blood serum. Are there, besides the complement, other substances capable of destroying microbes, substances exclusively and intimately linked to the white corpuscles? This question has as yet no ready answer, owing to the technical difficulties involved. It is likely, as appears from the research carried out by Pettersson and others, among whom we mention Max Gruber and his assistants, that substances of this kind, the endolysins of Pettersson or the leukins of Schneider, do exist in reality.

Quite apart from this intricate problem of the nature of microbicidal substances in the organism, it has been clearly shown that the power of the humours to kill infectious agents is restricted to the weakest microbes, also that the microbicidal part played by the white corpuscles and the phagocytes in general holds good for all infectious agents from which the body can have immunity.

As stated above, the bactericidal action of the complements is closely linked with another category of substances, the amboceptors of Ehrlich. They can not destroy nor damage the agents of disease. The amboceptors fasten on the agents and help the bactericidal action of the complements. The complements are localized in the phagocytes, whereas the amboceptors are to be found in the humours of the living organism and pass with ease to the fluids that accumulate round the microbes. Indubitably these are humoral substances that participate in the process of immunity. But the amboceptors are nothing else than phagocytic products excreted in the other fluid surroundings. Various researchers have established that the sources of the amboceptors are the spleen, bone marrow and lymphatic ganglia, in other words the very organs which are filled with phagocytes. It has even been shown by the experiments of Wassermann and Citron that the amboceptors arise in the places where infectious microbes have been introduced, places invaded by vast hordes of white corpuscles.

At the beginning of these investigations on the amboceptors, it was thought that the substances took part in the destruction of the microbes, but were completely alien to the system of phagocytic defence. Later it became clear that as products of the phagocytes, the amboceptors were only one of the terms of this defence.

The mechanism of the action of the amboceptors on microbes is not known in detail, not being manifest. In fact, the infectious agents impregnated with the amboceptors go on living and reproducing at the normal rate. They even keep their pathogenic power, but become capable of undergoing the action of the complements and more prone than before to be seized and enveloped by the white corpuscles.

In the case of the most fragile microbes, such as cholera vibrios and their kind, the combined action of the amboceptor and the complement leads to the destruction of the bacteria, whether accompanied or not by the granular transformation. But the great majority of pathogenic agents give greater resistance to a mixture of these two substances, as obtained in the organism or outside it in blood serum. In this case, there can be no question of bactericidal action as it is usually understood. But the microbes, impregnated with the amboceptor and the complement, fall an easy prey to the white corpuscles. The mixture of the two substances serves most of all to prepare the phagocytosis. Because of this characteristic, it has been called opsonin by Wright and bacteriotropin by Neufeld.

Persuaded of the relative unimportance of the humours as destructive agents to infectious microbes, the followers of the humoral theories have lately fallen back on the opsonins and the bacteriotropins, considered as humoral factors well to the fore in immunity. Not being able to do any damage at all to the microbes, they only modify them in so far as their absorption by the phagocytes are facilitated. Wright, who has been largely responsible for developing this argument, insists on the subordinate role of the white corpuscles that follow blindly the opsonin lead. He even judges the progress of immunity and cure according to the opsonic strength of the blood fluid. But, insisting on the preparation of the morbid agents by the opsonins, Wright admits the virtue of the phagocytes in ridding the organism of microbes. He even goes so far as to admit the existence of a spontaneous phagocytosis, which evolves without the aid of the opsonins. The opsonins would be important, however, in making the action of the white corpuscles more speedy and more sure.

It is a priori probable that the phagocytosis, namely the swallowing and digestion of the microbes by the phagocytes, is subject to favourable influences in the organism. Is not in intestinal digestion the secretion of the pancreatic juice favoured by other elements like secretin? There is thus no objection in principle to the theories of Wright and Neufeld. Only the methods on which the theories are based do tell against them. All research into opsonins and bacteriotropins has been conducted with humours and white corpuscles extracted from the organism and mixed with the microbes in glass test tubes. This method, which is very demonstrative, cannot render adequate account of the phenomena in the living body. The fate of the bactericidal theory of humours, based on experiments in vitro, should serve as a warning against placing too much trust in results obtained under these conditions. If it is true, as a great number of research workers now hold, that the opsonins and the bacteriotropins are mixtures in varying proportions of the complements and the amboceptors, one could easily understand that in the living organism things go on in quite another way than in test-tube experiments. We have already stressed the fact that the complements are linked to the phagocytes and only break away in exceptional circumstances.

In the investigations on the opsonins and bacteriotropins, investigations guided by humoral notions, on the whole only the power of the blood fluid to favour phagocytosis is regarded. The white corpuscles are taken as constant elements which can only obey the behests of the opsonins. Now the white corpuscles are living organisms, hypersensitive to external conditions and which admit of very great variation. The least change in the salt content of the fluid which surrounds them is enough to bring about significant modification of the phagocytosis. The white corpuscles of patients attacked by different diseases show a real diminution of their vital characteristics. The work of Parvu on the cells taken from a patient suffering from myelogenic leukemia showed more than half of the white corpuscles powerless to absorb the microbes.

Faced with such facts, some scientists stress the need to study not only the opsonic property of blood fluid but also to take into account the phagocytic function of the white corpuscles themselves. This idea is justified in so far as the destruction of the microbes is the main purpose of the organism’s fight against the agents of disease.

This destruction is carried out by live strong phagocytes. The absorption of the pathogenic bacteria, helped by the opsonins, is important but it is only the beginning of a series of phenomena that culminates in the digestion of the microbes within the phagocytes. In case the microbes that have been absorbed by the white globules do not die, owing to a deficiency of bactericidal substances, the organism is short on its defences and falls victim to the infection. It can happen that highly resistant microbes, such as the spores of tetanus bacilli, can be a long while in the white corpuscles without causing the terrible illness. The moment the corpuscles suffer some deleterious influence, for example cooling or overheating, then the spores that were hitherto imprisoned are set free and do straightway produce fatal tetanic cramps.

This is why, as several doctors have already pointed out, the power of the opsonins is not enough of itself in all cases to ascertain the organism’s level of resistance.

The phagocytes, subjected to influences favourable or unfavourable, have to reckon with the resistance of the agents of disease in their fight against the microbes. It can happen that the agents secrete substances which bring about deterioration in the white corpuscles to the point of dissolving them altogether. But in most instances, it is lesions which prevent the phagocytes absorbing and destroying the microbes. The substances that are directed against the phagocytes have been designated agressins by Bail. These are special poisons which attack the phagocytes in particular. In order for our defence cells to do their job properly, they must be protected against the microbial agressins. It has even been maintained that salutary phagocytosis can only take place with the aid of some preparatory action which is capable of neutralizing the agressins. This action would take its origin from elements of the body alien to the phagocytes. Series of experiments show that the white corpuscles are well fitted to absorb the agressins, without the agressins undergoing any modification. The work of Wassermann and Citron showed that the macerations of pathogenic microbes, prepared outside the organism, give a product which when introduced into the organism in quantity hinders phagocytosis. But these same microbes, generators of these agressins, are easily absorbed by the white corpuscles when the latter are in a state of reinforced activity.

The phagocytes are capable of fighting not only the agressins, I mean microbial poisons that work on the white corpuscles in particular, but even violent poisons that can kill the organism. This is a fact of prime importance in the study of immunity. After the wonderful discovery of bacterial counterpoisons by Behring, the opinion has been voiced that the defence of the organism which enjoys immunity relies above all on the neutralizations of the toxins, which are the poisons that the microbes produce. The microbes, following neutralization, forfeit the spearhead of the attack on the organism and descend to the level of absolutely harmless entities which in turn fall easy prey to the phagocytes. Phagocytosis would thus, although acting on live microbes, be reduced to an action of entirely secondary importance.

Numerous findings, achieved with care over the last few years, clean contradict this view. It has been shown that the white corpuscles entertain no fear of microbial poisons and are well fitted to absorb them and make them harmless. This was best illustrated by work on poisons in the body of infections microbes, going under the name of endotoxins. Besredka’s work is the most conclusive in this regard. He injected the abdominal cavity of guinea-pigs with dead bacilli of typhoid fever that could not cause the infection but contained typhoid endotoxin. The animals died within twelve hours. The same injection was given to animals whose abdominal cavity contained a large number of strong white corpuscles, and these took over the microbial bodies and their endotoxin and thus saved the animal from certain death.

Bail and Weyl got analogous results using a staphylococci poison. Injected by itself, this poison kills young rabbits within a matter of hours. Injected with a certain amount of white corpuscles, this poison is inactive and the animals live on.

Such examples could be multiplied. So it seems certain that the phagocytes do ensure immunity, not only from infections microbes but also from poisons produced by these microbes. Of all the organism’s elements, the phagocytes are distinguished by their poor sensitivity to toxicity. This is so true that white corpuscles are even able to withstand poisoning by mineral poisons. When endotoxins were not so well known and when the search for bacterial poisons soluble in the organism was fraught with great difficulty, Besredka went into the question of protection afforded by the white corpuscles with regard to arsenical preparations of small solubility. He selected arsenic trisulphide, the crystals of which are absorbed and modified by the phagocytes with avidity. He found that when the abdominal cavity of guinea-pigs contained a great quantity of white corpuscles, these cells saved the animals from fatal poisoning by phagocytising the crystals of the arsenic trisulphide. Similar findings have since been established on many occasions and it is now commonly held that many toxic and medicamental substances, introduced into the organism, are to be found in abundance in the interior of the white corpuscles. Lately Carles of Bordeaux has demonstrated the absorption of lead salts by white corpuscles. These salts were absorbed insoluble and became transparent within the phagocytes. When subjected to hydrogen sulphide vapour, however, they at once turned black. In absorbing poisons, the white corpuscles in their capacity as primitive elements comparatively non-sensitive to toxins, preserve the noble cells, such as those of the nervous system, the liver and other glands.

The sum of the very numerous facts established in the archives of science leaves no room to doubt the major part played by the phagocytic system, as the organism’s main defence against the danger from infectious agents of all kinds, as well as their poisons. Where natural immunity is concerned, and man enjoys this in respect of a large number of diseases, it is a question of the phagocytes being strong enough to absorb and make the infectious microbes harmless. It goes without saying that the phagocytic reaction is helped by every means at the organism’s command.

Thus, when the microbes penetrate, the white corpuscles make use of the dilatation of the blood vessels and the nervous actions that control this, in order to reach the battle field in the shortest possible time. Every influence that can trigger off the phagocytosis is naturally brought to bear.

In immunity achieved as a result of vaccinations or subsequent to an attack of the disease, the organism shows a series of modifications. Much stress has been laid on the growth in humoral properties under these conditions. In fact the blood fluid in these cases contains considerable amounts of amboceptors and bacteriotropins (very probably identical) which prepare the microbes for phagocytosis. But, as said above, the amboceptors are products of the phagocytes. Now to secrete great quantities in the humours, the phagocytes must be modified in the organism that has acquired immunity. This might have been expected a priori but it has not been easy to prove by conclusive evidence. Pettersson had the idea of introducing white corpuscles into the organism, originating from animals that had been vaccinated against certain microbes. He found that these elements do give real protection against doses of infectious microbes that are fatal several times over. On the other hand, the white corpuscles of an organism which does not have immunity are powerless to produce this result.

Salimbeni, in view of the outstanding import of this, began a series of experiments at the Pasteur Institute, with the aim of checking Pettersson’s findings. Using a method that allowed of great accuracy, he was able to confirm these findings and take them further. He showed that the white corpuscles of the immunized organism are a true source of protective substances, and that at a time when the blood fluid does not yet show any modification. In spite of successive washings, the phagocytes still ensured immunity. In the course of his research, Salimbeni proved that at the moment when the humours have already lost their protective powers altogether, the organism is still refractory and resists fatal doses of infectious microbes. This fact, together with other supporting evidence, leads to a conclusion of the greatest importance. Namely, that even in acquired immunity, the properties of the cells take pride of place over the humoral properties.

At this point, it may seem paradoxical that in spite of the serious modifications that follow acquired immunity, the white corpuscles show no augmentation of their function which may strictly be termed phagocytic. They absorb the infectious agents to the same extent as the white corpuscles taken from a normal organism and put into contact with the humours of the immunized organism. Ever since the first experiments of Denys and Leclef, those concerned have stressed the importance of this finding. It must not be forgotten that these experiments were conducted with white corpuscles taken from the organism and studied in vitro. In spite of all that has been said on this score, the objection is valid. Comparison is drawn between phagocytosis of the white corpuscles of an organism that has been subjected during weeks and months to injections of vaccine and all the while kept captive, and the white corpuscles of a fresh organism which has never been under attack. The conditions, as may be seen, are far from identical.

Even were it soundly established that the phagocytes in acquired immunity do not undergo any modification, to their power of absorbing microbes, this result would not in any way invalidate the general fact of augmentation in the defensive power of the phagocytic system. It need only be admitted in this instance that just as for acquired immunity there is no augmentation found in the production of the complements, so there is no augmentation in the property of enveloping. The strengthening of the defence would then be reduced to overproduction by the phagocytes of substances that prepare the way for phagocytosis.

The total of phenomena observed in immunity thus reduces to a series of biological acts, for example the sensitivity of phagocytes, their active movements directed to areas imperilled by the microbes, and a series of chemical and physical acts which bring about the destruction and the digestion of the infectious agents. Since a dozen years, under the impulse provided by the theories of Ehrlich, many men of science have tried hard to lay bare the inner mechanism of the phenomena of immunity. Ehrlich himself held that the amboceptors, which abound in acquired immunity, combine in determined proportions with the molecules of the complements on the one hand and with those of the microbes, i.e. their receptors on the other. Many field-workers, led by Bordet, fight this theory. According to them, the amboceptors are unworthy of the name, for they are not the chemical go-between of the complements and the microbes, but act on these like the mordant in tissue dyeing. Bordet also calls amboceptors by the name of sensitizing substances, on account of their property to facilitate the action of the complements on the microbes. The whole phenomenon falls in his eyes into the category of molecular absorption in varying extents.

The polemic on these two theories has been going on ten years. The problem of the inner mechanism of immunity is so delicate and complicated that it is not yet definitely resolved. It must however be said that many research workers find it fashionable to support the idea that the action of the organism on microbes is outside the picture of chemical phenomena strictly so-called, and is rather in the domain of the physical actions of the colloids, some of which spring from the microbes while others belong to the organism. Analogies are sought between substances that are observed in immunity and the colloids. Some are not far from saying that the complements are lipoids, analogous to those that come in to the constitution of animal organs.

All this research promises results of prime importance in the more or less near future. At the moment, what it amounts to is no more than incursions into a field thick with thorny problems. The place of the phagocytic system in immunity has however emerged from the stage of theory and is now doctrinal.

It is time to ask now if the notions acquired from so many years’ work and discussion yield practical application in medicine. This general law that in all cases of immunity the phagocytic reaction is pronounced, leads one to conclude that the degree of phagocytosis can be used in medical prognosis. From the beginning of our research on phagocytosis, we became convinced that the more the microbes were absorbed by the white corpuscles, then the more chance the animal had of surviving and making a complete recovery. Swiss veterinary expert, Zschokke, was the first to make use of this rule in the struggle against infectious mammitis in cows, which is an epizootic that causes serious deterioration in milk. He was able to show that plentiful phagocytosis of streptococci, which are the disease bearers of this sickness, is a good sign that all is going well. The fate of cows suffering from “gelber galt”, as mammitis is locally called, depends on the extent of phagocytosis. When this is insignificant or nil, the cows are written off as no longer productive of good milk. A whole system has been built up to determine the degree of phagocytosis and this is confirmed by findings on slaughtered animals. Although in most instances, the extent of the phagocytosis gave a precise indication, examples have been known of cows which did not recover although the majority of the streptococci was contained within the white corpuscles. These exceptions in turn led to new field-work on the part of Vrijburg. As was to be expected according to phagocytosis theory, for the organism to triumph over the infectious microbes, these must not only be absorbed by the white corpuscles but also utterly destroyed. There are cases where the streptococci of mammitis, after absorption by the phagocytes, demolish the cells and finish by being free to carry on their deadly work. To arrive at sound prognosis, the extent of the phagocytosis must be measured and the state of the phagocytes with the microbes within them must be known too.

This example of contagious mammitis should admonish those who think it enough to determine the opsonic strength to be able to judge how an illness or indeed immunity is faring.

In other diseases brought on by streptococci, the degree of the phagocytosis can also serve as a prognostic. Professor Bumm in Berlin uses this method to prognosticate puerperal fever. Strong phagocytosis indicates speedy recovery, while minimal or slight phagocytosis means the worst is to be feared.

In the treatment of illness by Dr. Wright’s vaccinotherapy, the phagocytosis shows the opsonic strength of the blood. It is thus a guide to the doctor. We said above that this method was coming to be joined by that of determination of the property of phagocytes, independently of the opsonic action in itself. For some time phagocytosis has been used with success in the diagnosis of certain infectious diseases.

Among the practical applications of the doctrine of phagocytosis mention must be made of the use in surgery of substances capable of bringing a large quantity of white corpuscles to areas under operation and open to infection. There are already surgeons in France and in Germany, who introduce into the abdominal cavity or under the skin of their patients either warmed blood serum or nucleic acid or other substance, with the object of bringing to the scene a protective army of phagocytes to ward the microbes off. The results achieved are so encouraging that it is possible to predict new progress in the approach to the dressing of wounds. At the opening of the new era in surgery, only the microbe was taken into account and the patients were soused in antiseptics. It was soon seen that these are poisons that spell danger to the organism under treatment. Antiseptics gave way to aseptics. Now it is known that phagocytosis is a valuable force in the organism’s defences, an attempt is being made to modify surgical methods by the adjunct of means that reinforce the number of the phagocytes.

Of the therapeutic methods that have emerged latterly, we note the process of Professor Bier. This consists in the systematic application of cupping-glasses and rubber strips to augment the veinous stasis round abscesses, furuncles and similar afflictions of many kinds. Cure is often achieved by this means with a rapidity that is little short of surprising. It has been asked what caused such success. Modern methods of research at their most refined have been used. The contradictions have not been entirely removed. But it is generally held that the phagocytosis is an important element in cure effected by the Bier method. The application of cupping-glasses and bands causes veinous stasis and thus an oedema is formed round the injured area. At the same time, a large number of white corpuscles come to the spot, and these serve to strengthen the phagocytosis. In a very recent treatise on this subject, the Japanese Dr. Schimodaira, working in a European laboratory and with no particular love of the phagocytic theory, has nevertheless been forced to admit that augmenting the phagocytic reaction in the use of the Bier method is one of the main factors effecting cure.

It is small wonder after so much evidence has been given on the valuable part played by the phagocytes, that research should concentrate on the conditions capable of strengthening phagocytic reaction. A number of works has recently been published on this topic. Among the substances that activate phagocytosis, mention can be made of quinine, a medicine much loved by medical practitioners. Grünspan’s research shows that weak solutions of two milligrams per hundred raise the power of phagocytosis to a marked degree, while solutions fifty times stronger give the opposite result. Neisser and Guerrini have studied a whole series of substances that stimulate phagocytic activity, among which they make especial reference to certain solutions of peptones. The chapter on stimulins that we opened a long time ago and that had lain forgotten has recently been put back on the map again. All means are used to augment the phagocytic reaction to ensure cure and immunity. How different by far from the ideas that were once sovereign in medicine. I remember forty years ago the famous Helmholtz having learned from Cohnheim that the pus corpuscles in inflammation come from the white corpuscles in the blood, taught, in accordance with the then current theories, that the accumulation of such elements constituted a danger to the organism, a danger that must be met by doses of quinine, capable of paralysing the movements of the white corpuscles. It is enough to compare this point of view with the actual concept of the benign role of the inflammatory reaction in general and of the phagocytic reaction in particular, to gather how far we have come.

The theory of phagocytes, laid down more than twenty-five years ago, has come under heavy fire on all sides. It is only of late that it has won recognition from the well-informed in all lands, and it is only as it were yesterday that it has begun to have practical use. We have thus the right to hope that for the future medicine will find more than one way to bring phagocytosis into play to the benefit of health.

I have attempted to outline the present state of a subject that may serve as an example of the useful purpose to be served by purely theoretical research. The study of the origin of the digestive organs in the lower animals, since long disappeared, has opened up the field little by little, leading to a new concept of immunity, to the quest for methods of fighting infection and ensuring resistance and recovery, of the organism.

In awarding me a prize for my research on immunity, the Nobel Committee has chosen to honour me for all my work done over twenty-six years, and in part carried out by my many pupils at the Pasteur Institute.

I express my deepest thanks to the Committee for this great distinction which gives me the greatest joy any savant can wish for. I have however one fear. Namely that the Committee is esteeming my work beyond its true worth. I take heart from the thought that it was the intention of the generous founder Alfred Nobel to reward men of learning who give their lives to knowledge without deriving any benefit from its practical applications.

From Nobel Lectures, Physiology or Medicine 1901-1921, Elsevier Publishing Company, Amsterdam, 1967

How to Manage Pests

Poison oak showing 3 leaflets with the central leaflet having a longer stalk than the other two.

Poison oak leaves and flowers.

Poison oak, also known as western poison oak (Toxicodendron diversilobum), is one of several members of the sumac or cashew plant family (Anacardiaceae) that are native to North America and are known to cause contact dermatitis. Other species include western poison ivy (T. rydbergii), eastern poison ivy (T. radicans), Atlantic poison oak (T. pubescens), and poison sumac (T. vernix). The weeping, itchy rash caused by these plants is the most common allergic contact dermatitis in North America, affecting 10 to 50 million Americans per year.

Western poison oak is the only species that occurs in California. Its distribution extends from British Columbia to the Baja California peninsula. In Washington and Oregon, poison oak is found mainly in the western regions of the states. In California it is widespread and grows in a wide range of habitats including coastlands, oak woodlands, rangelands, conifer forests, riparian areas, and brushlands, and occurs from sea level to about 5,000-foot elevation. Poison oak can also frequently be found in urban landscapes, parks, gardens, and recreational areas.


Being able to identify poison oak will help minimize contact and more importantly lessen the chance of an allergic reaction. In open areas under full sunlight, poison oak forms a dense, leafy shrub usually 1 to 6 feet high. In shaded areas, such as in coastal redwoods and oak woodlands, it grows as a climbing vine, up to 75 feet or more, supporting itself on other vegetation or upright objects using its aerial roots.

Despite its name, poison oak is not a true oak. Leaves of true oaks, which are superficially similar to poison oak, grow singly, not in groups. The adage &lsquo&lsquoleaves of three, let them be&rsquo&rsquo refers to each leaf of poison oak having three leaflets. Although a general truth, it is not a rule. Leaves normally consist of three leaflets with the stalk of the central leaflet being longer than those of the other two. Although uncommon, leaves can occasionally have five or seven leaflets, and in rare cases nine.

Each leaflet is 1 to 4 inches long with toothed or somewhat lobed edges. The surface of the leaves can also be varied, ranging from glossy to dull in color, thin to leathery in texture, and sometimes even hairy, especially on the lower surface. The diversity in leaf size and shape accounts for the Latin term diversilobum in the species name.

Poison oak is deciduous, which can make detection and identification extremely difficult in the winter and early spring when leaves are absent. In early spring, new leaves are green or sometimes light red. The leaves occur alternately, meaning they grow to the left then to the right along the stem. Plants lack thorns and spines on the leaves and stems, which can aid in identification. Poison oak produces small, white-green flowers at the point where leaves attach to the stem.

Whitish-green, round fruit form in late summer and can persist into fall and winter. The fruit lack hairs. In late spring and summer, the foliage is often glossy green and later turns attractive shades of orange and red. A similar common species, called skunkbush sumac (Rhus trilobata), resembles poison oak but does not cause dermatitis. It has hairy fruit and does not have the stalk on the central leaflet.

Poison oak is a long lived woody perennial plant. Seeds have a hard seed coat and can remain viable in the soil for many years. Once seeds germinate and the plants become established, plants can sucker from rhizomes (underground stems) and further spread in the adjacent area. In addition, vines that contact the ground often form roots, creating new plants that contribute to the lateral expansion. Over time a single plant can cover a very large area.

The leaves and stems provide a valuable food source for many animals including deer and livestock, while birds and other animals forage on berries without adverse effects. The passage of the hard-seeded fruit through the digestive tract facilitates germination by reducing the period of dormancy.


Poison oak thrives along roadsides and other areas where established vegetation is disturbed, in uncultivated fields, and on abandoned land. It also is a problem in wood lots, Christmas tree plantations, rangelands, and recreation areas. While it can reduce optimal grazing area in rangeland or pastures, the primary concern associated with poison oak is the allergic reaction it causes in many people.

All members of the genus Toxicodendron&mdashwhich includes poison oak, poison ivy, and poison sumac&mdashcan cause allergic contact dermatitis in humans. The allergy is caused by the plant oil urushiol (pronounced yoo-ROO-shee-all). Urushiol does not appear to cause serious allergic reactions in cats or dogs. Their coats tend to protect them from the oil, so while it's uncommon for pets to have a reaction to it, an allergic response can occur in areas where there's no hair or in hairless breeds with more exposed skin.

In California, the number of working hours lost as a result of dermatitis from poison oak makes it the most hazardous plant in the state. Approximately 50% to 75% of the adult population is sensitive to urushiol. In large urban areas, where these plants are less common, the prevalence is closer to 20%. Peak sensitization occurs between 8 and 14 years of age with infants not as easily sensitized as adults. Once a reaction occurs, repeated exposures further increase sensitivity. Conversely, long periods with no exposure will reduce an individual&rsquos susceptibility. There is also strong evidence to suggest children born to two urushiol-sensitive parents will also be sensitive.

Contrary to popular belief, coming in contact with poison oak doesn&rsquot mean a sensitive individual will get a rash. Urushiol is found in the stems, roots, leaves and skin of the fruits of these plants. Usually damage is required for plants to release the oil, therefore slight contact with uninjured leaves is innocuous. More vigorous activities such as weed eating, clearing brush, pruning, or trampling can result in injury and transfer the oil onto the skin, clothing, tools, or pets.

Urushiol is nonvolatile, dries quickly and can persist on objects and retain its ability to cause an allergic response for months or even years. This means that tools, clothing, pets, vehicles, and other objects that come in contact with the oil can continue to spread the oil. When poison oak is burned, the oils can disperse via the smoke particles. Breathing this smoke can cause severe respiratory irritation.

In the fall, leaves turn red and become enriched with urushiol which can result in higher levels of exposure. In winter as the leaves become dry and fall off, the oils are reabsorbed into the stems making the leaves non-allergenic. Bare stems in the winter can result in unintentional contact and if stems are damaged, oil can be released resulting in exposure.

There is currently no preventative treatment for contact dermatitis other than avoidance of exposure (recognition of the plant and wearing gloves, long pants, and long sleeves), use of skin blocking products, and washing with soap and water quickly after exposure.

Hyposensitization using shots or medicine to make one immune to poison oak were available at one time but were taken off the market when they were found ineffective. Other attempts have been made to immunize against poison oak including ingestion of the leaves. None of these measures has definite value either as preventive or as a cure, and sometimes they result in detrimental allergenic effect. Research in this area is ongoing and at the time of publication, a new drug (PDC-APB) is undergoing clinical trials as a vaccine to prevent poison oak dermatitis.

Tips for Preventing an Allergic Reaction

When a sensitive individual comes into contact with the allergen, the skin rapidly begins to absorb it. The key in minimizing or preventing an outbreak is to remove the oil from your skin as quickly as possible. Urushiol is easily degraded in water. However, the oil can be removed in significant amounts only if washed off immediately. At 10 minutes, 50% can be removed at 15 minutes, 25% at 30 minutes, only 10% and after 30 minutes, all of the oil has been absorbed.

The best way to remove the oil is forceful unidirectional washing with a damp washcloth and liquid dishwashing soap. The washcloth should be applied with repetitive, high-pressure, single-direction wipes under warm, running water. This provides the friction and heat necessary to remove the glutinous oil. Removing urushiol can be thought of as comparable to removing axle grease. The full-body wash should be performed for 3 rounds of about 3 minutes. Because it doesn&rsquot involve violent rapid back-and-forth scrubbing, or irritating products such as strong soaps, it does not cause significant irritation. This technique is simple, inexpensive and safer than high-potency topical and systemic corticosteroids.

Other research has shown that a mild solvent such as isopropyl (rubbing) alcohol poured over an exposed area then washed with plenty of cold water is also effective. If washing is not possible within 30 minutes, it is still worthwhile to wash at the first opportunity to avoid any continued exposure from contaminated clothing. Be sure to thoroughly wash your hands and especially under the fingernails, since they serve as the major route for transferring the oil to other parts of the body, especially the face. All exposed clothing, equipment, and pets should be washed thoroughly in soap and water.

If you wash with isopropyl alcohol or soap, be sure you are done working outside for the day as these products will remove your skin&rsquos protective oils, which help repel the plant toxin. Your body will not regenerate these protective oils for 3 to 6 hours. If re-exposure could occur within 6 hours, you will have better results washing with a washcloth and lots of water. Using only a small amount of water or disposable hand wipes is more likely to spread the oil than remove it.

There are several products available over-the-counter to help remove urushiol from your skin. Some of these include Tecnu, Zanfel, and various soaps. All these products have shown to be effective at removing urushiol oil from the skin.

Tips for Treating an Allergic Reaction

Within 1 to 6 days after exposure, skin irritation and itching will be followed by water blisters, which can exude serum. Contrary to popular belief, the serum does not contain urushiol and does not transmit the rash to other regions of the body or to other individuals. Variations in the time of appearance of rash and the severity of rash are caused by differences in the amount of oil absorbed and the skin thickness. Contact with latent oil is the reason new lesions develop weeks after first symptoms develop. The most common culprit for re-exposure are fingernails, clothing, tools, and pets. The dermatitis rarely lasts more than 10 days.

Don&rsquot scratch the blisters. Bacteria from under your fingernails can get into the wounds and cause an infection. The rash, blisters, and itch normally disappear within 1 to 2 weeks without any treatment.

  • Using wet compresses or soaking in cool water.
  • Applying over-the-counter (OTC) topical corticosteroid preparations or taking prescription oral corticosteroids.
  • Applying topical OTC skin protectants, such as zinc acetate, zinc carbonate, zinc oxide, and calamine to dry the oozing and weeping of poison ivy, poison oak, and poison sumac. Protectants such as baking soda or colloidal oatmeal relieve minor irritation and itching. Aluminum acetate is an astringent that relieves rash.
  • You have a temperature over 100°F.
  • There is pus, soft yellow scabs, or tenderness on the rash.
  • The itching gets worse or keeps you awake at night.
  • The rash spreads to your eyes, mouth, genital area, or covers more than one-fourth of your skin area.
  • The rash does not improve within a few weeks.
  • The rash is widespread and severe.
  • You are known to have a severe reaction.
  • You have difficulty breathing.


The primary ways of managing poison oak plants are mechanical removal by hand pulling, which is not recommended for individuals who are sensitive to this plant, and treatment with herbicides. Maintaining a healthy cover of desirable vegetation will reduce potential invasion. This is easiest where you have available irrigation and regularly cultivated soil.

Poison oak is a native species in the western United States. As such, several indigenous insects and pathogens are already present. Typically, biological control is not an option with a native species. Furthermore, in most areas, poison oak is not a pest, but rather a natural component of the plant community.

Avoid burning poison oak, since it creates a serious health hazard and does not effectively reduce infestations. Grazing by sheep and goats can be effective in small areas. Deer, horses, and cattle will also graze poison oak when the foliage is young, before the plant flowers.

Mechanical Control

Physically remove plants located in a yard or near houses through hand pulling or mechanical grubbing using a shovel or pick. It is essential to remove the entire plant including its roots. Remove plants in early spring or late fall when the soil is moist and it is easier to dislodge rootstocks. Grubbing when the soil is dry and hard usually will break off the stems, leaving the rootstocks to vigorously resprout. Detached and dried brush can still cause dermatitis, so bury or stack the plant material in an out-of-the-way location or take it to a disposal site. Again, never burn poison oak.

Ideally, anyone engaged in hand pulling poison oak should have a high degree of immunity to the allergen. Whether you are sensitive or believe you are immune, wear appropriate protective clothing, including washable cotton gloves over plastic gloves. Wash equipment, tools and all clothing thoroughly, including shoes, after exposure.

Other forms of mechanical control have not proven successful. Tractors with a brush rake or bucket can be useful for removing the above ground growth, but often leave pieces of roots that can readily resprout. In some cases, brush removal in late summer, when plants experience moisture stress, can slow their ability to recover. However, using large equipment to clear land creates a perfect environment for new seedling establishment, making follow-up control essential.

Mowing is not an effective method for controlling poison oak. Mowing can release oil particles in the air similar to burning, so mowing is not recommended. Lopping mature plants near the base will provide poor control unless performed repeatedly throughout the season. Lopping can lead to vigorous resprouting. Lopping can be combined with an herbicide treatment to increase control.

For home gardeners, using a rototiller repeatedly throughout the year can be an effective technique for controlling poison oak in a garden area. Rototilling or cultivating an area only once can fragment the rhizomes and spread the poison oak.

Chemical Control

Post-emergent herbicides containing the active ingredients triclopyr, glyphosate, or imazapyr are available for controlling poison oak. These herbicides can be used alone or in combination. Pest control companies for hire may have access to several other active ingredients for poison oak control (See RESOURCES). Depending on the product, herbicides may be applied as foliar sprays, cut-stump treatments, or as basal bark treatments.

When using herbicides, be sure to prevent them from getting on desirable plants. Because glyphosate is a nonselective pesticide, it will damage or kill other vegetation. Triclopyr is a broadleaf herbicide that will not injure grasses but will damage or kill other broadleaf plants. Imazapyr is nonselective, like glyphosate, and applications may also leave an herbicidal soil residue.

Herbicide active ingredients, particularly glyphosate, can readily attach to dust or soil particles, thus reducing their effectiveness. Although not typically a problem, dust can cover plants growing near roadsides. If dust is a concern, time the application after a rain event so the leaves are clean.

The best time to apply triclopyr is late spring or early summer when plants are actively growing. When air temperatures are higher than 80°F, it is better to use glyphosate or the amine formulation of triclopyr, since the ester form is subject to vaporization.

The effectiveness of herbicides depends on three factors&mdashtiming, achieving good coverage, and using a proper concentration.

Foliar Sprays. Depending on the herbicide being used, foliar application to poison oak is either done in late spring when the plant is actively growing or in the late summer after flowering.

Foliar herbicide sprays can be applied using one of two methods. The first is spray-to-wet, where all leaves and stems should glisten following an application. Coverage, however, should not be to the point of runoff. The other method is a low-volume foliar application called drizzle. This technique uses a higher concentration of herbicide, but sprayed at a lower volume. This method is advantageous in dense shrubbery or where access is limited. To achieve proper coverage, spray the herbicide uniformly over the entire canopy in a &ldquodrizzle&rdquo pattern, using a spray gun.

For spray-to-wet applications, products containing at least 41% glyphosate as the active ingredient can provide good to excellent control of poison oak when applied at 2.5 ounces of product per gallon of water (2% of the total solution). Some products available for use in the home landscape with this concentration of active ingredient are Roundup Pro, FarmWorks Grass & Weed Killer 41% Glyphosate Concentrate, RM43 Total Vegetation Control, Compare-N-Save Grass & Weed Killer Concentrate, and Remuda Full Strength.

Glyphosate products that have a lower concentration of active ingredient, such as Roundup Concentrate (18% active ingredient), will require 6 ounces of product per gallon of water (4.5% of the total solution) for effective control using the spray-to-wet application method.

Triclopyr is available in either amine or ester formulations, with triclopyr ester being more effective on poison oak, since absorption of the herbicide into the foliage and stems is not as good with the amine form. Products containing a minimum of 61% active ingredient of the ester formulation can provide good to excellent control when applied at 1.2 to 6.4 ounces of product per gallon of water (1% to 5% of the total solution) as a spray-to-wet application. One such product with this concentration is Brushtox Brush Killer with Triclopyr. Other ester formulations with less concentrate are also available including Crossbow. Mixing triclopyr ester with commercially available seed oils can offer better penetration. One available seed oil product is Hasten-EA modified vegetable oil concentrate. Mix this at 1.25 ounces of product per gallon of herbicide solution (1% of the total solution).

Triclopyr is also available in the amine formulation. Products available include Bayer Bio Advanced Brush Killer Plus, Ortho Brush-B-Gon Poison Ivy and Poison Oak & Brush Killer, and Monterey Brush & Vine Control. These products contain 8% active ingredient and will require 4 to 8 ounces of product per gallon of water (3% to 6% of the total solution), depending on the product used.

When used in a drizzle application on dense canopies or steep topography, glyphosate formulated as a product with 41% active ingredient can provide good to excellent control of poison oak. It should be applied at 13 ounces of product per gallon of water (10% of the total solution).

Triclopyr ester can also be applied using a drizzle application. Products containing 61% active ingredient should be applied using 13 ounces of product (10% of the total solution) and 25 ounces of seed oil (20% of the total solution) per gallon of water.

Remember that although the drizzle technique uses a higher concentration of herbicide, you are applying it at a lower volume. One gallon of mixed herbicide solution should adequately treat one-half acre of densely populated poison oak.

Cut-Stump Application.Cut-stump treatments are most effective in spring during active plant growth or in the fall. Immediately after cutting, apply the herbicide to the cut surface with a paint brush, spray bottle, or plastic squeeze bottle. Delaying application will result in poor control, because the cut surface will quickly dry, preventing movement of the chemical into the plant. For small diameter stems, cut the stems with loppers or clippers and paint or sponge the herbicide solution onto each cut end.

For triclopyr ester products containing 61% active ingredient, use 1 part product and 4 parts seed oil. The 8% amine formulation works well undiluted.

Glyphosate can be applied as a cut-stump application. If using a product containing 18% glyphosate, use undiluted. For products that contain 41% glyphosate, make a 1:1 solution of the product and water.

Cut stump applications can be made in the spring or fall. Follow similar timelines as given for glyphosate and triclopyr under foliar treatments.

Basal Bark Application. Apply concentrated forms of triclopyr ester to the trunks of poison oak using a backpack sprayer, spray bottle, or wick applicator. Thoroughly cover a 6 -to 12-inch band around the basal section of the stem. Make basal bark applications almost any time of the year, even after leaves have senesced. For triclopyr ester products with 61% active ingredient, the application ratio is 20% product in 80% seed oil carrier. To make a quart (16 oz) of solution in a spray bottle, add 3.2 ounces of product to 12.8 ounces of seed oil. Glyphosate and the amine formulation of triclopyr provide poor control using this technique.

One application of an herbicide does not always completely control poison oak. Re-treat when new, sprouting leaves are fully expanded, generally when the plants are about 2 feet tall. Watch treated areas closely for at least a year and re-treat as necessary.

In areas near rivers or streams, it is important to use the proper herbicide products. Only a few formulations of glyphosate, triclopyr and imazypyr are permitted for use in or near bodies of water. Be sure to read the label for allowed uses. It is a violation of Federal law to use a pesticide in a manner inconsistent with its labeling.

Home gardeners and professional applicators should always wear appropriate protective equipment, as identified in the precautionary statements of the herbicide product label.



DiTomaso JM, Kyser GB et al. 2013. Weed Control in Natural Areas in the Western United States. Weed Research and Information Center, University of California. UC ANR Publication 3547. Oakland, CA.

Epstein WL, Byers VS. Poison Oak and Poison Ivy Dermatitis&ndashPrevention and Treatment in Forest Service Work. USDA Forest Service Equip. Dev. Ctr. Pub. 8167 2803. Missoula, MT, Forest Service Equip. Dev. Ctr.

Neill BC, Neill JA, Brauker J, Rajpara A, Aires D.J. 2018. Post-exposure prevention of toxicodendron dermatitis with early forceful unidirectional washing. Journal of the American Academy of Dermatology. Feb 1. pii: S0190-9622(18)30171-3

Pekovic DD. 2016. Vaccine against Poison Ivy Induced Contact Dermatitis, A Lingering Scientific Challenge. Int J Vaccines Vaccin 2(1): 00023.


Pest Notes: Poison Oak
UC ANR Publication 7431

AUTHORS: Scott Oneto, UC Cooperative Extension, Central Sierra and Joseph DiTomaso, Emeritus, Plant Sciences, UC Davis.

EDITOR: B Messenger-Sikes

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Statewide IPM Program, Agriculture and Natural Resources, University of California
All contents copyright © 2021 The Regents of the University of California. All rights reserved.

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