A complete treatment of the subject of this chapter would require many volumes. There are some toxicological data available on over 20 000 industrial chemicals, including pharmaceuticals and consumer products of all types, although for a very large proportion of these the data reflect only relatively short-term, high-dose exposures. The number for which both comprehensive animal and epidemiological studies are available probably does not exceed a few hundred. The rest have some intermediate degree of toxicological characterization.
The data base is growing all the time and new regulatory initiatives, especially in the EU, are intended to accelerate that growth in the near future.
Numerous compendia are available and can be consulted if there is a need to acquire comprehensive knowledge on specific substances (see Sources and recommended reading). The intention of this chapter is not to provide anything even remotely complete about any given chem- ical. It is instead simply to illustrate with concrete examples the many toxicological principles and concepts we have been discussing, and to show the diverse ways chemicals of many different types can bring about harm, and the conditions under which they do so. We cover most of the significant targets of toxicity, provide a little background on the biological characteristics of those targets – their structure and functioning – and then show the several ways excessive chemical expo- sure can cause harm.
The specific type of harm we call cancer is left to later chapters, because it is so important and because there are so many aspects of can- cer initiation and development that are unique. It would be a mistake
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to interpret the separate treatment of cancer as an indication that it is a far more important toxicological issue than those discussed in this chapter. Cancer as a disease phenomenon is obviously of enormous importance, but it may well be that the types of chemicals that are the central subjects of this book are less important causes or promoters of the cancer process than are those associated with various “lifestyle”
choices (which are still “environmental” but which entail sources of risk that include large elements of personal choice and that are other- wise distinct from those on which we are focusing). We are learning that the types of substances that are the principal subjects of this book may be more significant contributors to other manifestations of human disease, namely those covered in this chapter.
We begin with the killers – toxic agents of many types that have the capacity to cause serious injury or death at relatively low dose delivered over relatively brief exposure periods. These are what we rightly call “poisons.” We then turn to the “slow poisons,” the many substances that produce their most serious effects when delivered over long periods of time, at doses well below those that are immediately dangerous. When we discuss the “slow poisons” we do so by categoriz- ing them by their “targets”: respiratory toxicants, liver toxicants, sub- stances that damage the nervous or reproductive systems, and so on.
There are other ways to categorize toxicants. Many texts categorize them by chemical class (the metals, aldehydes and ketones, aromatic hydrocarbons, and so on). You will also find toxicants categorized by use or source (food additives, pesticides, air pollutants, cosmetics ingredients), and even by the mechanistic phenomena that cause their toxicity (metabolic poisons, DNA-damaging agents, cholinesterase inhibitors). Each of these various categories has value in the appropri- ate context, and the approach taken here is, I believe, the most useful for the ultimate use to which we shall be putting the knowledge: the conduct of toxicological risk assessments.
Poisons from nature
Botulinum toxins are a collection of protein molecules that are extraor- dinarily poisonous to the nervous system. These toxins1are metabolic
1 The name “toxin” is correctly applied to naturally occurring protein molecules that produce serious toxicity. There has been a tendency to broaden the use of this term to include other categories of toxic agents. We shall adhere to the proper usage in this book.
93 products of a common soil bacterium,Clostridium botulinum, which is frequently found on raw agricultural products. Fortunately, the bac- terium produces its deadly toxins only under certain rather restricted conditions, and if foods are processed properly so that these condi- tions are not created, the toxins can be avoided. Food processors have to be extremely careful with certain categories of food – canned foods having low acidity, for example – because the slightest contamination can be deadly. In 1971 an individual succumbed after consuming a can of vichyssoise made by the Bon Vivant soup company. A massive recall of canned soups resulted. The Bon Vivant company vanished soon after this event; botulinum toxin not only killed the customer, but also exterminated the company.
Botulinum toxins can belethalat a single (acute) dose in the range of 0.000 01 mg/kg b.w.! This amount of toxin is not visible to the naked eye: about a million lethal doses per gram of toxin! The initial symptoms of botulism typically appear 12–36 hours after exposure and include nausea, vomiting, and diarrhea. Symptoms indicating an attack on the nervous system include blurred vision, weakness of facial muscles, and difficulty with speech. If the dose is sufficient (and a very, very small dose can be), the toxicity progresses to paralysis of the muscles controlling breathing – the diaphragm. Death from botulism thus comes about because of respiratory failure. Botulinum toxins are regarded as the most acutely toxic of all poisons.
To illustrate the famous Paracelsusan claim that the dose distin- guishes a drug from a poison, we can point to botox, an extremely dilute form of botulinum toxin that effectively softens skin wrinkles and also, at least temporarily, eliminates the spastic muscle contrac- tions associated with conditions such as cerebral palsy. In 1965 at the age of 37, the famed concert pianist, Leon Fleisher, lost the use of his right hand. His condition, called focal dystonia, involves a type of neurological “misfiring” that causes some muscles to contract uncon- trollably (in Fleisher’s case those in certain fingers of his right hand).
The pianist, after a few years of botox injections (which he has to repeat every six months), recently released his first recording since the 1960s in which he plays pieces requiring two hands (he found a living teaching and playing pieces written for the left hand).
Sucrose, which we all know as table sugar, can also be acutely toxic.
I cannot locate any evidence of humans being killed by a dose of table sugar, but toxicologists can force enough into rats to cause death. A lethal dose of sucrose in rats is in the range of 20 000 mg/kg b.w. That is about as “non-toxic” as chemicals get to be. If humans are equally
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Table 4.1 Conventional rating scheme for lethal doses in humans
Probable lethal oral dose for humans Toxicity rating Dose (mg/kg b.w.) For average adult 1 Practically non-toxic more than 15 000 More than 1 quart 2 Slightly toxic 5000–15 000 1 pint–1 quart 3 Moderately toxic 500–5000 1 ounce–1 pint
4 Very toxic 50–500 1 teaspoon–1 ounce
5 Extremely toxic 5–50 7 drops–1 teaspoon 6 Supertoxic less than 5 less than 7 drops
sensitive, one would have to eat more than 3 pounds of sugar at one time for it to be lethal.
The two substances – sucrose and botulinum toxins – differ in lethal- ity by about 10 billion times! The acute lethal doses of most chemicals fall into a much narrower range, but there are many substances near the two extremes of this distribution of lethal doses.
Clinical toxicologists have found it convenient to rate chemicals according to their potential to produce death after a single dose. The conventional rating scheme is as shown in Table4.1.
Clearly, if a person has to ingest a pint or more of a chemical before his life is seriously threatened, this chemical is not a likely candidate for use in homicide or suicide, and is highly unlikely to be ingested accidentally in dangerous amounts. Chemicals rated in categories 5 or 6, however, need to be extremely carefully controlled.
Keep in mind that the rating chart presented above concerns only acute, lethal doses, received by the oral route. It only provides a very limited picture of the toxic properties of chemical agents, and should never be used as the sole basis for categorizing chemicals.
Some chemicals that are “supertoxic” by the above rating have no known detrimental effects when they are administered at sublethal doses over long periods of time, while others in the same category and in lower categories do produce serious forms of toxicity after repeated dosing.
Some naturally occurring “extremely toxic” and “supertoxic”
chemicals are listed in Table 4.2, along with their environmental sources and toxicity targets. Some of these are toxins found in the venom of poisonous snakes or in the tissues of certain species of
95 Table 4.2 Some supertoxic chemicals of natural origina
Chemical Source Principal toxicity target
Botulinum toxin Bacterium Nervous system
Tetrodotoxin Puffer fish (fugu) Nervous system Crotalusvenom Rattle snake Blood/nervous system
Naja naja Cobra Nervous system/heart
Batrachotoxin South American frog Cardiovascular system
Stingray venom Stingray Nervous system
Widow spider venom Black widow Nervous system
Strychnine Nux vomicab Nervous system
Nicotine Tobacco plant Nervous system
aSome of these chemicals, particularly the venoms, are protein or protein-like compounds that are deactivated in the gastrointestinal tract; they are poisonous only when injected directly into the blood stream.
bThe seed of the fruit of an East Indian tree used as a source of strychnine.
animal. Doctor Findlay Russell, who has made enormous contribu- tions to our understanding of the nature of animal toxins, their modes of biological action, and the procedures for treating people who have been envenomed or poisoned, estimates that there are about 1200 known species of poisonous or venomous marine animals, “countless”
numbers of venomous arthropods (spiders), and about 375 species of dangerous snakes (out of a total of about 3500 species).
We have been speaking of both “venomous” and “poisonous” ani- mals, and there is a distinction between the two. A venomous animal is one that, like a snake, has a mechanism for delivering its toxins to a victim, usually during biting or stinging. A poisonous animal is one that contains toxins in its tissues, but cannot deliver them; the victim is poisoned by ingesting the toxin-containing tissue.
An interesting and important example of an animal poison is par- alytic shellfish poison (PSP). This chemical, which is also known as saxitoxin and by several other names as well, is found in certain shell- fish. But it is not produced by shellfish; it is rather a metabolic product of certain marine microorganisms (Protista). These microorganisms are ingested by the shellfish as food, and their poison can remain behind in the shellfish’s tissue. Paralytic shellfish poison is not a pro- tein, but a highly complex organic chemical of most unusual molecular structure.
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Shellfish accumulate dangerous levels of PSP only under certain conditions. Typically, this occurs when the microorganisms undergo periods of very rapid growth, resulting from the simultaneous occur- rence of several favorable environmental conditions. This growth, or
“bloom,” frequently imparts a red color to the affected area of the ocean, and is referred to as ared tide. Shellfish growing in a red tide area can accumulate lethal amounts of PSP.
Red tides (and some with other colors as well) occur with some reg- ularity in certain coastal waters of New England, Alaska, California, and several other areas. If it is the type of tide that can produce PSP or other toxins, public health officials typically quarantine affected areas to prevent harvesting of shellfish. In some areas of the Gulf of Alaska, large reservoirs of shellfish cannot be used as food because of a persistent PSP problem.
Paralytic shellfish poison, like botulinum toxin, is a neurotoxic sub- stance and can also affect certain muscles, including the heart, which are under nervous system control. Some poisoned humans who have recovered from the effects of PSP have described the early stages of intoxication as not at all unpleasant: a tingling sensation in the lips and face and a feeling of calm. Those who die from PSP ingestion do so because of respiratory failure.
The first successful method for measuring the amount of PSP in shellfish was published in 1932. The procedure used was a bioassay.
The bioassay for PSP was simple. Extracts from shellfish suspected of contamination were fed to mice. The poison was measured in “mouse units.” A mouse unit was the amount of toxin that would kill a 20 gram mouse in 15 minutes. Crude, but nevertheless effective at telling public health officials when shellfish were too toxic to eat.
The plant kingdom is another source of some unusually toxic chem- icals. A few examples are presented in Table4.3, along with a descrip- tion of some of their biological effects.
Infants and preschoolers are the most frequent victims of plant tox- ins. Their natural curiosity leads them to put all sorts of non-food items into their mouths, and berries, flowers, and leaves from house and yard plants are often attractive alternatives to spinach. The num- ber of deaths from consumption of poisonous plants is not great, but the number of near-deaths is; about 10% of inquiries to poison control centers concern ingestion of house, yard, and wild plants, including mushrooms. Among the house plants dumbcane (species of dieffenbachia) and philodendrons are prominent, and a fair number
97 Table 4.3 Poisonous properties of some common plants
(The specific chemicals involved are in some cases not known)
Plant Effects
Water hemlock Convulsions
Jimson weed Many, including delirium, blurred vision, dry mouth, elevated body temperature
Foxglove, lily-of-the-valley, oleander
Digitalis poisoning – cardiovascular disturbances
Dumbcane (dieffenbachia) Irritation of oral cavity
Jonquil, daffodil Vomiting
Pokeweed Gastritis, vomiting, diarrhea
Castor bean Diarrhea, loss of intestinal function, death
Poison ivy, poison oak Delayed contact sensitivity (allergic dermatitis)
Potatoes, other solanaceous plantsa Gastric distress, headache, nausea, vomiting, diarrhea
a The Solanaceae include many species of wild and cultivated plants, the latter including potatoes, tomatoes, and eggplants. All these plants contain certain natural toxicants called solanine alkaloids. The levels found in the varieties used for food are below the toxic level, although not always greatly so. Potatoes exposed to too much light can begin to grow and to produce excessive amounts; the development of green coloring in such potatoes (chlorophyll) indicates this growth. Storing potatoes under light, particularly fluorescent light, is to be discouraged.
of poisonings arise from jade, wandering Jew, poinsettia, schifflera, honeysuckle, and holly.
Children are also especially vulnerable for a reason touched upon in Chapter2. Consider the family of mushroom toxins known as amatox- ins. Almost all mushroom-related deaths in North America are caused by these toxins, which are metabolic products ofAmanita phalloides.
These toxins are slightly unusual because symptoms appear only after 12 hours following ingestion; they include vomiting, diarrhea, and very intense abdominal pain. Ultimately the toxins cause liver injury that can be serious enough to cause death.
The lethal dose of amatoxins is in the range of 1 mg/kg b.w. For an adult weighing 70 kg, a total of about 70 mg needs to be consumed to cause death (1 mg/kg × 70 kg). For a one-year-old child weighing
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10 kg, only about 10 mg needs to be ingested to create a life- threatening intake of the toxins. Small body size is highly disadvanta- geous.
Synthetic poisons
Perhaps the most prominent and well-studied class of synthetic poisons are so-calledcholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmis- sion – the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neuro- transmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase; the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junc- tions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscu- lar junctions the results are tremors and, at sufficiently high doses, paralysis and death.
Two important classes of cholinesterase inhibitors are the organophosphates and the carbamates, a few of which are widely used insecticides. Two such insecticides are chloropyrifos and carbaryl (structures shown). They are highly effective insecticides and, if used properly, appear to be without significant risk to humans (although the use of chloropyrifos and some other members of the class is somewhat controversial).
Cl
Cl O
Cl P
O S
O CH2
CH2
C H3
C H3
Chloropyrifos
O C NH
O C
H3
Carbaryl
99 Interestingly, much work has been devoted to the development of substances in the class of cholinesterase inhibitors that have exceed- ingly high toxicity; substances that also have properties (such as volatility and sufficient but not excessive environmental stability) that make them useful as agents of warfare. Most of those now stockpiled were first developed during World War II. Sarin and VX are perhaps the most well-known members of this class of compounds that have been especially designed to kill people.
O P
O CH CH3 F
CH3 CH3
Sarin (nerve gas)
P S
O O
CH2 CH3
CH2CH2 N HC
CH3 CH
CH3
C H3
CH3 CH3
VX (nerve gas)
Of course these and other “nerve gas” agents are available to terrorists. Sarin, for example, was used twice during the 1990s by Japanese terrorists in Matsumato and Tokyo. Not only were the typical symptoms of acute poisoning, including death, observed, but follow-up studies revealed a number of serious delayed effects. The question of delayed effects remains significant for the whole large class of cholinesterase inhibitors. Drugs such as atropine are used to treat anticholinesterase poisoning; atropine reduces the effects of excessive acetylcholine by altering the particular receptors at which it normally acts to transmit nerve impulses.
As in the case of botulinum toxins, certain cholinesterase inhibitors are effective medicines. Physostigmine, a naturally occurring carba- mate derived from the calabar bean, has been used as a glaucoma treat- ment since the late nineteenth century. Neostigmine, another carba- mate, is used to overcome the acetylcholine deficiency that is the cause ofmyasthenia gravis. Another anticholinergic agent called tacrine is effective at alleviating dementia in some subtypes of Alzheimer’s dis- ease. All of the medicines can, at high doses, cause poisoning. Again, old Paracelsus is seen to be correct.
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Poisonings from industrial accidents
Although industrial chemicals, or the incidental by-products of indus- trial society, do not create quite the risk of acute lethality that some natural and deliberately synthesized poisons do, there are some that can cause considerable toxicity after a single exposure. Most of these acute exposures are created by industrial or transportation accidents, which are not infrequent. To minimize the damage accidental releases such as these might cause, it has become important to use the toxicity rating classification discussed earlier and to label industrial chemicals accordingly to ensure appropriate care is taken in handling, storing, and transporting them. Of course, there have been industrial accidents involving releases sufficiently large to cause death, sometimes to work- ers, sometimes to nearby residents or passers-by. The worst example of this type of event took place during the night of December 3, 1984, at Bhopal, India. Approximately 40 tons of methyl isocyanate (a very simple organic chemical used in the synthesis of an important pesticide and having the structure shown) were released into the atmosphere, killing more than 2000 people and injuring many more.
C H3 N
C O Methyl isocyanate
For a series of chemicals that are commonly involved in accidental release of one type or another, the EPA has developed Acute Expo- sure Guidelines, called AEGLs. They are intended for use in guiding actions under emergency conditions, and are expressed as air con- centrations that are associated with certain adverse outcomes after specific and relatively short-term exposure periods, from minutes up to 8 hours. The agency has found three types of AEGLs useful: one that describes the air concentration producing effects that are non- disabling (AEGL-1); those that specify the air concentration that is disabling and which could prevent people from removing themselves from the affected area (AEGL-2); and the concentration that could be life-threatening (AEGL-3). The AEGLs are derived from available information obtained from the study of accidental and occupational exposures, and from animal experiments.
Although there have been a number of industrial releases of hydrogen chloride (HCl) that have led to life-threatening effects or