INTRO CHEMISTRY I

CHEM 1405

CHEMICAL TOXICOLOGY

TOXICOLOGY

The study of the effects of poisons, their detection and identification, and their antidotes.

NATURAL POISONS

Poisons from plant and animal sources were well known in the ancient world.

Many aboriginal tribes still use various natural poisons for hunting and warfare. Curare, used by certain South American tribes to poison their arrows, is a notorious example.

In addition to poisons produces by plants, there are many toxins produced by animals such as snakes. Many insects and lots of microorganisms also produce poisons.

CORROSIVE POISONS

Corrosive poisons can be separated into two groups:

Ozone, peroxyacetyl nitrate (PAN), and the other oxidizing components of photochemical smog probably do their main damage through the deactivation of enzymes. The active sites of enzymes often incorporate the sulfur containing amino acids cysteine and methionine.

Oxidizing agents can break bonds in many other chemical substances in a cell. Such powerful agents as ozone are more likely to make an indiscriminate attack than to react in a highly effective way.

POISONS AFFECTING OXYGEN TRANSPORT and OXIDATION PROCESSES

Certain chemical substances prevent cellular oxidation of metabolites by blocking the transport of oxygen in the bloodstream or by interfering with oxidative processes in the cells. These chemicals act on the iron atoms in complex protein molecules.

Carbon monoxide (CO) - binds tightly to the iron atoms in hemoglobin, blocking the transport of O2.

Nitrates - found in ground waters and diminish hemoglobin's ability to carry O2.  Microorganisms in the digestive tract reduce nitrates to nitrites. The resulting oxygen deficiency disease is called methemoglobinemia, known in infants as “blue-baby syndrome”.

Cyanides, compounds that contain a CN- group, are among the most notorious poisons in both fact and fiction.

Cyanides act quickly and are powerful. It takes only about 50mg of HCN or 200-300mg of a cyanide salt to kill.

Cyanide acts by blocking the oxidation of glucose inside the cell.

Any antidote for cyanide poisoning must be administered quickly. Providing 100% oxygen to support respiration can sometimes help. Sodium nitrite is often given intravenously to oxidize iron atoms in the enzymes back to the active Fe3+ form. Sodium thiosulfate (“hypo” used in developing photographic film) is then used if time permits. The thiosulfate ion transfers a sulfur atom to the cyanide ion, converting it to the relatively innocuous thiocyanate ion.

Unfortunately, few victims of cyanide poisoning survive long enough to be treated.

FLUOROACETIC ACID

The body generally acts to detoxify poisons, but it can also convert an essentially harmless chemical to a deadly poison. Fluoroacetic acid is one such compound. Our cells use acetic acid to produce citric acid, which is then broken down in a series of steps, most of which release energy. When fluoroacetic acid is ingested, it is incorporated into fluorocitric acid. The latter effectively blocks the citric acid cycle by tying up the enzyme that acts on citric acid. Thus, the energy-producing mechanism of the cell is shut off and death comes quickly.

HEAVY METAL POISONS

Metals with densities of at least five times that of water are called heavy metals. Many heavy metals are toxic, but lead, mercury, and cadmium are especially notable

Mercury presents a hazard to those who work with it because its vapor is toxic.

Because mercury is a cumulative poison (it takes the body about 70days to rid itself of half of a given dose), chronic poisoning is a threat to those continually exposed.

British antilewisite (BAL) acts by chelating (from the Greek chela meaning “claw”) Hg2+ ions, surrounding the ions so that they are tied up and cannot attack vital enzymes.

The bad news is that the effects of mercury poisoning may not show up for several weeks. By the time the symptoms- loss of equilibrium, sight, feeling, and hearing- are recognizable, extensive damage has already been done to the brain and the nervous system. Such damage is irreversible.

Metallic mercury does not seem to be very toxic when ingested (swallowed). Most of it passes through the system unchanged.

Mercury vapor is quite hazardous when inhaled, particularly when exposure takes place over a long period of time.

Lead and its compounds are quite toxic. Metallic lead is generally converted to Pb2+ in the body. Lead can damage the brain, liver, and kidneys. Extreme cases can be fatal.

Adults can excrete about 2 mg of lead per day. Most people take in less than that from air, food, and water, thus generally do not accumulate toxic levels. If intake exceeds excretion, however, lead builds up in the body and chronic irreversible lead poisoning results.

Lead poisoning is usually treated with a combination of BAL and another chelating agent called ethylenediaminetetraacetic acid (EDTA).

As in mercury poisoning, the neurological damage done by lead compounds is essentially irreversible. Treatment must be begun early to be effective.

Like mercury and lead, cadmium (as Cd2+ ions) is quite toxic. Cadmium poisoning leads to loss of calcium ions (Ca2+) from the bones, leaving them brittle and easily broken. It also causes severe abdominal pain, vomiting, diarrhea, and a chocking sensation.

NERVOUS SYSTEM and NERVE AGENTS

Some of the most toxic substances known, act on the nervous system. Signals are shuttled across synapses between cells by neurotransmitters. Neurotoxins can disrupt the action of a neurotransmitter in several ways: by interfering with its synthesis or transport, by occupying the transmitter’s receptor site, or by blocking degradation of the transmitter.

One such chemical messenger is acetylcholine (ACh). It activates the postsynaptic cell by fitting a specific receptor and thus changing the permeability of the cell membrane to certain ions. Once ACh has carried the impulse across the synapse, it is rapidly hydrolyzed to acetic acid and relatively inactive choline in a reaction catalyzed by an enzyme, acetyl cholinesterase.

The receptor cell releases the hydrolysis products and is then ready to receive further impulses. Other enzymes, such as acetylase, convert the acetic acid and choline back to acetylcholine, completing the cycle.

Nerve Poisons and the Acetylcholine Cycle

Various substances disrupt the acetylcholine cycle at three different points, as illustrated by the following examples.

Botulin, the deadly toxin produced by Clostridium botulinum (an anaerobic bacterium) found in improperly processed canned food, is a powerful ACh antagonist; it blocks the synthesis of ACh. With no messenger formed, no messages are carried. Paralysis sets in and death occurs, usually from respiratory failure.

Curate, atropine, and some local anesthetics act by blocking receptor sites. In this case, the message is sent but not received. In the case of local anesthetics, this can be good for pain relief in a limited area, but these drugs, too, can be lethal in sufficient quantity.

Anticholinesterase poisons act by inhibiting the enzyme cholinesterase.

Nerve Poisons and the Acetylcholine Cycle

Various substances disrupt the acetylcholine cycle at three different points, as illustrated by the following examples.

ORGANOPHOSPHORUS COMPOUNDS (insecticides and nerve gas)

Organic phosphorus insecticides are well known nerve poisons. The phosphorus-oxygen linkage is thought to bond tightly to acetylcholinesterase , blocking the breakdown of acetylcholine. Acetylcholine therefore builds up, causing receptor nerves to fire repeatedly.  This over stimulates the muscles, glands, and organs. The heart beats wildly and irregularly, and the victim goes into convulsions and dies quickly.

 The nerve poisons are among the most toxic synthetic chemicals known (although still not nearly as toxic as the natural toxin botulin). They are inhaled or absorbed through the skin, causing a complete loss of muscular coordination and subsequent death by cessation of breathing. The usual antidote is atropine injection and artificial respiration. Without an antidote, death may occur in 2-10 min.

The phosphorus-based insecticides malathion and parathion are similar to the warfare nerve agent but far less toxic.

German discovered toxic agents during WWI while researching insecticides. These agents are anti-cholinesterase.  The nerve agent was called tabun (agent GA) - fruity odor.

The US has developed other nerve gases:

Antidote is atropine (another nerve poison with the opposite effect).  These nerve agents are the most toxic synthetic compounds known (not not nearly as toxic as botulin).

LETHAL DOSE

Some substances are much more poisonous than others. In order to quantify toxicity, scientist use the   term LD 50(lethal dose for 50%) to indicate a dosage that kills 50% of a population of test animals.

Usually LD50 values are given in terms of mass of poison per unit body weight of the test animal.

The larger the LD50 value, the less toxic the substance.

LIVER

The human body can handle moderate amounts of some poisons. The liver is able to detoxify some compounds by oxidation, reduction, or coupling with amino acids or other normal body chemicals.

Perhaps the most common route is oxidation. Ethanol is detoxified by oxidation to acetaldehyde, which in turn is oxidized to acetic acid and then to carbon dioxide and water.

Highly toxic nicotine from tobacco is detoxified by oxidation to cotinine.

Cotinine is less toxic than nicotine, and the added oxygen atom makes it more water soluble, and thus more readily excreted in the urine, than nicotine.

The liver is equipped with a system of enzymes called P-450 that oxidize fat-soluble substances (which are otherwise likely to be retained in the body) into water-soluble ones that are readily excreted.

Note that liver enzymes simply oxidize, reduce, or conjugate. The end product is not always less toxic.

Methanol is oxidized to more toxic formaldehyde, which then reacts with proteins in the cells to cause blindness, convulsions, respiratory failure, and death.

The same enzymes that oxidize alcohols deactivate the male hormone testosterone. Build-up of these enzymes in a chronic alcoholic leads to a more rapid destruction of testosterone. Thus, we have the mechanism for alcoholic impotence, one of the well-known characteristics of the disease.

Benzene, because of its general inertness in the body is not acted upon until it reaches the liver. There it is slowly oxidized into epoxide.

The epoxide is a highly reactive molecule that can attack certain key proteins. The damage done by this epoxide sometimes results in leukemia.

Carbon Tetrachloride (CCl4) is also quite inert in the body. But when it reaches the liver, it is converted to the reactive trichloromethyl free radical (Cl3C•), which in turn attacks the unsaturated fatty acids in the body. This action can trigger cancer.

CARCINOGENS

Carcinogen is something that causes the growth of tumors.

A tumor is an abnormal growth of new tissue and can be either benign or malignant.

WHAT CAUSES CANCER?

Most people seem to believe that synthetic chemicals are a major cause of cancer, but the facts indicate otherwise. Like overall deaths, most cancers are caused by lifestyle factors. Nearly two-thirds of all cancer deaths in the United States are linked to tobacco, diet, or lack of exercise with resulting obesity.

Some carcinogens, such as sunlight, radon, and safrole in sassafras, occur naturally. Some scientists estimate that 99.99% of all carcinogens that we ingest are natural ones. Plants produce compounds to protect themselves from fungi, insects, and higher animals, including humans. Some of these compounds are carcinogens found in mushrooms, basil, celery, figs, mustard, pepper, fennel, parsnips, and citrus oils

Carcinogens are also produced during cooking and as products of normal metabolism. Because carcinogens are so widespread, we must have some way of protecting ourselves from them.

HOW CANCERS DEVELOP

Some carcinogens chemically modify DNA, thus scrambling the code for replication and for the synthesis of proteins.

Genetics play a role in the development of many forms of cancer. Certain genes, called oncogenes, seem to trigger or sustain the processes that convert normal cells to cancerous ones.

We also have suppressor genes that ordinarily prevent the development of cancers. These genes must be inactivated before a cancer develops. Suppressor gene inactivation can occur through mutation, alteration, or loss. In all, several mutations may be required in a cell before it turns cancerous.

CHEMICAL CARCINOGENS

ANTICARCINOGENS

If the food we eat has many natural carcinogens, why don’t we all get cancer?  Probably because other substances in our food act as anticarcinogens.  Antioxidant vitamins are believed to protect against some forms of cancer, and the food additive butylated hydroxytoluene (BHT) may give protection against stomach cancer.  Certain vitamins also have been shown to have anticarcinogenic effects.

The evidence for the anticarcinogenicity of the vitamins taken as supplements is less conclusive; and in the case of β-carotene, even contradictory.

TERATOGENS

Teratogens are substances that cause birth defects.

HAZARDOUS WASTES

A hazardous waste is one that can cause or contribute to death or illness or that threatens human health or the environment when improperly managed.  For convenience, hazardous wastes are divided into four types: reactive, flammable, toxic, and corrosive.

The best way to handle hazardous wastes is not to produce them in the first place.  Many industries have modified manufacturing processed to recover energy or materials.

If a hazardous waste cannot be used or incinerated or treated to render it less hazardous, it must be stored in a secure landfill.