The Most Toxic Substance

Everything from dioxin (an environmental contaminant) to plutonium (a synthetic radioactive element) has been called the most toxic material ever known or made. Looking at the LD50 alone and ignoring for the moment that some people will be tolerant and some susceptible, the substance generally considered most toxic is the botulinum toxin. This toxin causes the disease called botulism, or botulism poisoning, and it has an LD50 of 0.00001 mg/kg, meaning that one gram of this substance would be enough (using simple assumptions and calculations) to kill roughly a million adult men.

The toxin itself is a protein produced by the bacteria Clostridium botulinum. The bacteria is anaerobic, meaning that it cannot survive in the presence of oxygen. Botulism poisoning can result from ingesting canned food that is infected with the bacteria. Such cans often have a bloated, bulging appearance. Once infected food is swallowed, the toxin is rapidly absorbed into the bloodstream. It acts as a neurotoxin, meaning that it attacks nerve function. In this case the toxin prevents the release of the neurotransmitter called acetylcholine. As a result one of the symptoms of botulism poisoning can be paralysis, as the muscles are unable to contract without the acetylcholine being present to transmit the signal down the nervous system. Often death occurs because the muscles used to breathe are paralyzed. Other symptoms, which appear within a few hours of ingestion, include nausea, vomiting, headache, weakness, and blurred vision. An antitoxin has been developed for botulism that can counteract the deadly paralysis, but survival usually depends on an early diagnosis and aggressive treatment to keep the patient breathing and nourished while treatments and time are allowed to work.

56 drugs, poisons, and chemistry who swallows 37 aspirin tablets all at once will die? No, the LD50 is an average across a population, and as such, susceptible women would die taking fewer, while tolerant women could take more and survive. Even with these considerations the LD50 provides a quantitative measure of potential harm that is invaluable to a toxicologist. It allows scientists to compare the relative toxicity, on average, of materials such as table salt and aspirin.

If the same calculations are performed for the table salt, the LD50 for an average woman comes out to be about 178 g, approximately 15 times as much as the lethal dose calculated for aspirin. This amount of salt (178 g) is equivalent to a little more than six ounces, well in excess of the contents of a typical salt shaker, or about a quarter of the familiar round boxes that salt is sold in. Because saltwater induces vomiting, it is hard to imagine anyone being able to swallow this much salt without throwing up, making it very difficult to ingest enough at one sitting to die.

Although both aspirin and salt are toxic, the harmful dosage of each is high, and the danger is minimal. In fact, most people would not even identify salt or aspirin as poisonous. For comparison, the LD50 for a highly poisonous material such as potassium cyanide (KCN) is on the order of approximately 1 mg/kg of body weight, which translates to 59 mg for the hypothetical woman weighing 130 pounds. A baby aspirin tablet weighs 80 mg. A fatal dose of arsenic trioxide (AsO3), a famous poison from ancient to Victorian times, would be about 106 mg. One of the most toxic substances known, the botulinum toxin, has an LD50 of 0.00001 mg/kg, or 0.59 microgram (^g; a microgram is 1 one-millionth of a gram), a speck of material far too small to see without the aid of a powerful microscope.

OTHER FACTORS IN TOXICITY

The amount of poison (the dose) is just one aspect of toxicity. There are other factors that must be considered when trying to determine how toxic a substance is to the person ingesting it. These include the following:

• inherent toxicity of the substance

• method (mode) of ingestion

• time over which the dose was administered

• rate of elimination compared with the rate of ingestion

• the person's health, age, and genetic factors

As shown with the earlier aspirin example, the size of the person ingesting the substance matters. Given that the material is distributed throughout the body once ingested, the smaller the person, the more concentrated the toxin will be in the blood or tissues. An analogy would be a tablespoon of sugar dissolved in a small teacup versus a large mug. Although it is the same amount of sugar, the tea in the teacup will taste much sweeter since it is dissolved in a smaller amount of tea than in the mug; thus, it is much more concentrated.

The inherent toxicity depends on how a drug or poison works, or its MOA. In general, the more toxic a substance is, the more critical the bodily process it attacks. The botulinum toxin is a potent neurotoxin, meaning that its mechanism is to attack the nervous system. Specifically, it impedes the release of a neurotransmitter resulting in the inability of neurons to transmit signals. As a result some of the symptoms of botulism poisoning include weakness of the muscles and paralysis, starting with eye muscles. Interestingly, tiny doses of the toxin are now used for cosmetic reasons because of these effects. Injection of the toxin into facial muscles can counteract wrinkling. This is known as the Botox injection procedure. Thus, even a substance called the "most toxic" has practical uses.

Carbon monoxide (CO), a toxic gas that results in many accidental poisonings each year, works by a different mechanism. It binds to hemoglobin in the blood much more strongly than oxygen does. As more CO is inhaled, more oxygen is displaced from the blood. Death can occur when about 50 percent of the oxygen has been displaced; death occurs as a result of suffocation (asphyxia, or lack of oxygen). The effects of CO poisoning are reversible if the poisoned person is given pure oxygen. The mechanisms of toxicity of CO and botulinum are completely different and lead to different inherent toxicities for these two substances.

There are many ways for drugs and poisons to enter the body (see table, page 59)

There are many ways for drugs and poisons to enter the body (see table, page 59)

There are many ways in which a toxic substance can be introduced into the body. Ingestion by mouth (swallowing) has been assumed so far, but it is only one of several ways by which a toxic substance can enter the body. While some seem odd ways to be poisoned, all are common ways in which drugs and medicines are administered. A new flu vaccine, for example, can be administered via a nasal inhaler. The mode of ingestion can influence how quickly an effect is observed. Direct injection of a substance into a vein can result in an almost immediate response

MODES OF iNGESTiON

Number Mode

(as indicated in figure)

1. Injection into the tissue under the skin

2. Injection into a vein (intravenous)

3. Absorption through the skin (dermal)

4. Injection into a muscle

5. Inhalation of a gas or aspiration (inhalation of liquid)

6. Ingestion into the stomach (oral)

7. Dissolution below the tongue (sublingual)

8. Absorption through the mucous membranes of the nose (nasal)

9. Absorption through the eyes since the substance is rapidly distributed by the bloodstream to the body. Similarly, inhalation usually produces a faster response than ingestion into the stomach as the substance is delivered to the lungs where there is direct contact between the lung tissue and the blood system.

The time over which a substance is ingested is another critical factor in determining its toxicity. In the body an ingested material is subject to many processes. Once the substance is introduced, it is absorbed and distributed via the circulatory system throughout the body and to different organs, such as the liver, where metabolic processes occur. Metabolism changes the chemical form of the substance, creating new materials (metabolites) that follow the same path as the original. Water-soluble forms of the substance can be excreted in the urine, sweat, or tears, while gaseous by-products can be exhaled. Materials that are fat soluble or otherwise bound up in the body are retained, sometimes for years or a lifetime. If the original substance is water soluble, it is not unusual for some of it to be excreted in its original form.

How long this transformation and elimination scheme takes is critical in determining the toxicity of the substance. If the rate of elimination is fast, toxicity decreases, as even large doses can be removed relatively quickly. If the rate of elimination is slow, materials will build up, increasing the toxicity. Depending on the balance of the rate of ingestion versus

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