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Which would you prefer to drink—a cup of caffeine or a cup of trichloroethylene? Chances are good that your response was “caf-feine.” Caffeine occurs naturally in coffee, tea, and chocolate, and it is added to sodas and other types of drinks and foods. Trichloroethylene, onthe other hand, is a solvent used to dissolve grease, and it is also a commoningredient in glues, paint removers, and cleaning fluids. Trichloroethylene doesnot occur naturally in the environment, but it is sometimes found as a pollut-ant in groundwater and surface water.
So, which would be better to drink? Believe it or not, caffeine is more poisonous than trichloroethylene. At low concentrations, caffeine is used as afood additive because of its effects as a stimulant—it helps people to stayawake and to feel lively. However, at concentrations higher than those foundin food products, caffeine can cause insomnia, dizziness, headaches, vomit-ing, and heart problems. In studies of laboratory animals, high doses of caf-feine have caused birth defects and cancer.
Does this mean you should think twice about reaching for that cup of Toxicity indicates
cocoa or tea? No, there’s more to the story than that. What it does mean is that many common substances found in food and drinks are toxic, or poison- ous, if you eat or drink large enough quantities. The amount of caffeine in a normal human diet does not cause illness, but just 50 times this amount isenough to be fatal.
Trichloroethylene is less toxic over the short term than caffeine, but it is not harmless. In fact, long-term exposure may cause a variety of health prob-lems, including cancer as well as damage to liver and kidneys.
A N Y C H E M I C A L C A N B E T OX I CAny chemical can be toxic if you eat, drink, or absorb too much of it. Evenwater can kill you if you drink too much too quickly! Back in the early 1500s, aSwiss doctor named Philippus Aureolus Theophrastus Bombastus vonHohenheim-Paracelsus wrote: All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.
A S S E S S I N G T O X I C R I S K : S T U D E N T E D I T I O N S E C T I O N 1 : U N D E R S T A N D I N G T O X I C R I S K Paracelsus was one of the first people to recognize that a chemical can be harmless or even beneficial at low concentrations but poisonous at higher ones. That is why it is so important to take medicine in the correct dosage.
Even vitamin pills can kill you if you swallow too many in too short a period of time. For example, vitamin D is an important nutrient, but it also is ahighly toxic chemical. In tiny amounts it is good for you, but taking morethan the recommended dose can cause serious health problems, includingkidney stones, high blood pressure, deafness, and even death.
A R E N AT U R A L C H E M I C A L S S A F E R ?Synthetic chemicals are made by people rather than nature. They are com-posed of natural elements such as carbon, hydrogen, nitrogen, and chlorine.
Toxins are toxic
We manufacture synthetic compounds to use in a wide variety of products such as cleaners, deodorants, food additives, and pesticides.
Many people believe that chemicals produced by nature are safe and syn- thetic ones are harmful. They fear that synthetic chemicals will cause cancer and that any exposure to them must be dangerous. It is true that some syn-thetic chemicals cause cancer, and others are highly toxic. But it also is truethat many synthetic chemicals are harmless at doses normally encounteredin food, water, air, and other sources.
The same is true for natural chemicals—they range from relatively harm- less to highly toxic. Some plants and animals create toxic chemicals calledtoxins, either for self-defense or for assistance in catching their prey. Thinkabout rattlesnakes, scorpions, and poison ivy—each produces a natural toxinthat is hazardous to humans as well as to other organisms in the environment.
The dose is the total
The distinction between synthetic and natural is not always clear-cut because people can manufacture many chemicals that occur in nature. Forexample, the vitamin C in an orange is identical to ascorbic acid created in a laboratory. There are additional benefits to eating an orange that you do not get from taking a vitamin C tablet, but the vitamin itself is identical from H O W M U C H I S T O O M U C H ?To measure a chemical’s short-term toxicity, scientists carry out somethingcalled a “dose/response” study. The word dose refers to the total amount of asubstance to which an individual is exposed through the mouth, lungs, orskin. Your total dose of a chemical includes the amount of the chemical thatyou eat, either by itself or contained in food or drinks, and the amount thatyou inhale with the air you breathe. It also includes absorption through yourskin, which could happen if the chemical were dissolved in your bath water Exposure means
or included in your shampoo or skin care products. All of these sources to- gether make up your exposure to the chemical.
Exposure to a toxic chemical can be either intentional or unintentional.
For example, a person who chooses to swallow too many pills is taking an intentional overdose. Someone who accidentally becomes poisoned by N A T I O N A L S C I E N C E T E A C H E R S A S S O C I A T I O N C H A P T E R 1 : T H E D O S E M A K E S T H E P O I S O N eating contaminated food receives an unintentional overdose. Similarly, a smoker intentionally inhales whatever substances are contained in cigarette response, the
smoke, whereas nearby people get exposed unintentionally when they inhale The word response refers to the changes in living things caused by expo- sure to a specified chemical or mixture. Typically, the higher the concentra- tion of a toxic compound, the more powerful its effect. Scientists study thisrelationship by carrying out dose/response experiments to determine the re-sponse of laboratory organisms to various doses of a test chemical.
Dose/response experiments are called bioassays (the word assay means test, A bioassay uses
and bio is short for biological). For any given chemical, the question is, “How much is too much?” At low enough doses, the test organisms are not harmed and may even benefit. At high enough doses, they all die. For each chemical, there is an intermediate range in which some individuals will be affectedand others will not.
In a typical dose/response bioassay, laboratory rats are each fed a single dose of the chemical being tested. Some rats get an extremely high dose, andothers receive doses ranging from moderate to very low. Exposure to the A dose/response
chemical occurs only on the first day, but the experiment continues for 14 days bioassay measures
in order to give the organisms time to react. At the end of this period, scien- tists count the number of dead rats and note any health-related responses in those that are still alive. At the highest dose, it is likely that all of the rats willhave died. At the lowest dose, most of the rats probably will have survived. Ifthe experiment has been properly designed, there should be several dosesthat have killed some but not all of the exposed rats.
The end result is a number called the LD50, which stands for the lethal The LD50 is the dose
dose for 50% of the treated organisms. In other words, half of the rats that received the LD50 dose have died by the end of the 14-day test period. LD50s are expressed in terms of milligrams of the chemical per kilogram of body The experiment should also include a control group. The rats in the con- trol group are treated exactly the same as the other rats except that they arenot exposed to the chemical being tested—their dose of this chemical is zero.
Within any species, some individuals will die at lower doses than others.
When rats are fed caffeine, some may die after eating only 100 mg, whileothers may tolerate 20 or 30 times this amount. Humans show these samekinds of differences. A cup of coffee at bedtime may have no effect on oneperson, yet may keep someone else awake through the whole night. There-fore, rather than relying on individuals, toxicity tests are based on groupresponses. The more individuals tested, the better the chance of accuratelyestimating the LD50 and of identifying low doses to which only the mostsensitive individuals respond.
Topic: bioassaysGo to: www.sciLINKS.orgCode: ATR02 A S S E S S I N G T O X I C R I S K : S T U D E N T E D I T I O N S E C T I O N 1 : U N D E R S T A N D I N G T O X I C R I S K F I G U R E 1 .1A Typical Dose/Response Cur ve Follow the arrows to see how the percentage of deaths is used to figure out the LD50 (thedose representing death of 50% of the treated organisms).
LD50 experiments measure lethal dose—the amount of a chemical that will kill 50% of the test organisms. But of course chemical exposures canaffect organisms in ways other than death, such as causing nausea, dizziness, skin rashes, or paralysis. When scientists carry out LD50 experiments, they also look for health effects such as these and record the doses at which sucheffects occur.
The more toxic the compound, the lower its LD50 . That makes sense if youthink of poisons—the more poisonous a chemical is, the less it takes to kill you.
For caffeine, the LD50 is roughly 200 mg in laboratory rats. For trichloroethyl-ene, it is over 7,000 mg. This means that on average, rats can survive eatingover 35 times as much pure trichloroethylene as caffeine. (This is a 14-day testand does not consider possible long-term impacts on health and survival.) It only took a little! This is the message behind the story of LorettaBoberg, a 62-year-old woman from Wisconsin who always tastes foodbefore serving it to company. In this case, the company can be verythankful she did.
When Mrs. Boberg opened a jar of home-canned carrots last January, she dipped in a finger to taste the juice. Not liking the taste,she served home-canned beans to her guests instead. Within two days,Mrs. Boberg became dizzy and had difficulty walking. At first, hospitalstaff thought she had suffered a stroke because of her slurred speechand muscle weakness. The doctor did ask her if she had eaten anyspoiled food lately, however. Too weak to speak, Mrs. Boberg wrote”carrots“ on a piece of paper.
N A T I O N A L S C I E N C E T E A C H E R S A S S O C I A T I O N C H A P T E R 1 : T H E D O S E M A K E S T H E P O I S O N If this physician had not suspected botulism, even though he had seen only a few cases, Mrs. Boberg would probably have died. Thetoxin moved through the respiratory system, paralyzing her muscles.
A sample from the jar was fed to a laboratory mouse and it diedinstantly. The road to recovery for this lady was very slow.
Mrs. Boberg used a boiling water canner for the carrots that gave her botulism. Yes, this was the same method she had used—and only byluck had gotten away with—for the past 44 years. This year she was notso lucky. If, like Mrs. Boberg, you are canning low-acid foods such asvegetables (except tomatoes), red meats, seafood, and poultry in aboiling water canner or by the open kettle method, you may wish tothink twice before taking another chance.
Botulin, the compound that came close to killing Mrs. Boberg in the story above, is one of the most highly toxic chemicals known. It is created by bac-teria in improperly canned foods. People eating these foods suffer a severeform of food poisoning called botulism. As you can tell by comparing LD50values in Table 1.1, the compound that causes botulism is a million timesmore toxic than cyanide, and twenty million times more toxic than caffeine.
In its pure form, less than one drop of botulin toxin is enough to kill 500adult humans.
To get an idea what LD50 numbers mean, you can compare them to the amounts it would take to kill a typical human adult (see Table 1.2).
The LD50 values in Table 1.1 are based on experiments in which the com- pounds were fed to rats. LD50 values should always include information aboutthe type of animal and how it was exposed to the chemical being tested. Oth-erwise, it is impossible to interpret what the values mean or to compare themto values reported by other scientists.
For some compounds, there is a big difference in LD50 values from one species to another. Dioxin is a good example. The LD50 for dioxin is 5,000 times higher for hamsters than for guinea pigs. How could this be? Many factors affect how sensitive each species will be to a particular compound.
One of these factors is how the chemical gets metabolized. How much getsabsorbed into the animal’s blood, or stored in its liver, kidneys, or other tis-sues? How much passes right through and is excreted? How much gets con-verted into other chemical forms? The answers to these questions may varyfrom one species to another.
For example, a human being would have a hard time dying from eating too much chocolate. This is not true for dogs—eating just a few chocolatebars can be fatal to dogs because they cannot digest and break down thechemicals in chocolate in the same way that humans do.
A S S E S S I N G T O X I C R I S K : S T U D E N T E D I T I O N S E C T I O N 1 : U N D E R S T A N D I N G T O X I C R I S K T A B L E 1 .1Let hal Doses of Some Common Com pounds An extremely toxic compound formed bybacteria in improperly canned foods; causesbotulism, a sometimes fatal form offood poisoning A cancer-causing chemical created by moldon grains and nuts; can be found in somepeanut butter and other nut andgrain products A highly poisonous substance found inapricot and cherry pits and used in industrialprocesses such as making plastics,electroplating, and producing chemicals An essential part of the human diet but toxicin doses higher than those found in normalhuman diets The addictive agent that occurs naturally intobacco and is added to some cigarettes tomake them more addictive A compound that occurs naturally in cocoaand coffee beans and is a commonfood additive Alcohol in beer, wine, and otherintoxicating beverages A solvent and a common contaminant ingroundwater and surface water supplies An ingredient in citrus fruits such as oranges,grapefruits, and lemons Sugar, refined from sugar cane or sugar beets * These LD50s are based on oral ingestion by rats. They represent single doses that cause death of 50% of the treatedanimals within 14 days of exposure. LD50s are expressed in terms of milligrams of the substance per kilogram of bodyweight (mg/kg).
N A T I O N A L S C I E N C E T E A C H E R S A S S O C I A T I O N C H A P T E R 1 : T H E D O S E M A K E S T H E P O I S O N T A B L E 1 . 2Tox i c i t y C a t e g o r i e s U s e d f o r H u m a n Po i s o n s Aspirin(acetylsalicyclic acid)Salt (sodium chloride) Many animals, including dogs and humans, will vomit if they eat some- thing disagreeable. Rats and other rodents cannot vomit. Does this mean we should not use rodents in laboratory tests of chemical toxicity? Obviously they do not represent an exact model of how a person might respond to the same chemical. However, they do provide information that we can use to make limited conclusions about possible health effects on people.
Another concern related to use of laboratory animals for toxicity testing is the issue of animal rights. This is a complicated issue. Some people find itunethical to carry out experiments that may cause suffering or death of thetest animals. However, we all want to be confident that we will not becomesick, blind, or otherwise injured by the medicines, cleaning products, cos-metics, and huge range of other chemicals that we use on a daily basis.
Over the past few decades, scientists have developed a variety of new techniques to reduce the number of laboratory animals used in toxicologyexperiments. For example, some tests are carried out on single cells or onblood samples rather than on whole organisms. However, it has not beenpossible to eliminate the need for animal experiments. This is because thereis no guarantee that the response of molecules, cells, or tissues will provide areasonable model of the response of whole animals or humans.
Topic: animal experimentsGo to: www.sciLINKS.orgCode: ATR03 A S S E S S I N G T O X I C R I S K : S T U D E N T E D I T I O N S E C T I O N 1 : U N D E R S T A N D I N G T O X I C R I S K L O N G - T E R M V E R S U S S H O R T - T E R MT OX I C I T YFor most of human history, concern about the toxic effects of chemicals hasfocused on poisons that cause a rapid death. The earliest descriptions of hu-man life include stories about use of toxic plant and animal extracts—to coatarrows and spears used in hunting or fighting battles, or to create poisonousdrinks used to kill prisoners. These are examples of acute toxicity, the effectsof a single exposure to a toxic compound. LD50 experiments are designed toassess acute toxicity by measuring the short-term response of test organismsto a single dose of a chemical. Acute toxicity experiments provide useful in-formation but give a limited view of overall toxicity because they addressonly short-term responses to single doses.
Acute effects are
For some chemicals, the same total dose can be either deadly or harmless, depending on the rate of exposure. For other chemicals, this is not true, andeven tiny doses can add up to toxic concentrations over time. This is because our liver and kidneys work to break down and get rid of toxic chemicals, but these systems work better for some types of chemicals than others.
Lead is an example of a chemical that builds up in our bodies over time rather than getting broken down or excreted. Lead poisoning has been linked with stunted growth and mental retardation in children. These are not sud-den effects, but ones that develop gradually with long-term, low-level expo-sures to lead in air, food, and drinking water. Children living in homes withlead paint receive additional doses when they eat chips of paint or breathedust-filled air. Even though the daily doses may be quite low, lead accumu-lates in bones. When the concentrations become too high, lead poisoningdamages the nervous system and kidneys, causing problems such as hearingloss and mental retardation.
For many other types of chemicals, low daily doses do not cause problems such as these, and toxic effects occur only with short-term exposure to rela-tively large doses. For example, the oxalic acid found in rhubarb and spinachis harmless at the low concentrations found in these foods, but it would leadto kidney damage or death if you managed to eat 10 to 20 pounds of thesefoods at one meal.
Alcoholic drinks work the same way. A person who drinks too many drinks in a short period of time may die from acute alcohol poisoning. At therate of only one drink per day, that same total amount of alcohol might dolittle or no harm. At this slower rate, most people’s livers would have time tobreak down the alcohol rather than allowing it to build up to harmful levelsin the body. However, “most people” does not include everyone, and thereare some individuals with extra sensitivity to the toxic effects of any particu-lar chemical. In the case of alcohol, pregnant women are cautioned not todrink because of the heightened sensitivity of their unborn children toalcohol toxicity.
Within limits, our bodies can break down or get rid of many types of toxic compounds before they harm our health. However, it is possible to N A T I O N A L S C I E N C E T E A C H E R S A S S O C I A T I O N C H A P T E R 1 : T H E D O S E M A K E S T H E P O I S O N expect too much of our bodies. With continued exposure to a toxic chemical,the liver can become damaged. Alcoholics frequently suffer from this prob-lem, as do people who have had long-term exposure to toxic compoundsthrough their work or through living in a contaminated environment.
In recent years, people have become increasingly concerned about the Chronic effects
effects of long-term exposure to relatively low doses of contaminants. These are called chronic effects. If you lived in a house with a leaky furnace, you might be exposed to either acute or chronic carbon monoxide poisoning. Acute poisoning would occur if your house were tightly sealed, with so little venti-lation that carbon monoxide fumes could build up to lethal levels. If your house were better ventilated, you would be more likely to suffer chronic effects such as headaches and fatigue from exposure to lower concentrationsof the toxic fumes.
T E S T I N G C H R O N I C T O X I C I T YThe easiest way to test chemical toxicity is to count how many test organismssuffer serious health effects or die when exposed to large doses. However, formost types of environmental pollution, these acute toxicity measurements do not provide answers to the questions we are interested in asking. For ex- ample, we might wonder whether it is harmful to drink water that containslow concentrations of a chemical such as trichloroethylene. The concentra- tions are not high enough to cause acute poisoning, but we would also want to know whether it might be dangerous to drink the water every day for many years. Would this cause a disease such as cancer or asthma? Would itresult in birth defects, reduced growth rates, or lowered intelligence in chil-dren? These questions concern chronic toxicity.
To measure acute toxicity, you count how many test animals die within a couple of weeks after a single exposure to a chemical. For chronic toxicity,we want to know how the animals’ health is affected by continuing exposureover a much longer time period. Rats, mice, or other lab animals are fedrelatively low doses of the test chemical each day for months or years. Dur-ing this time, the experimenters look for various effects such as loweredgrowth rates, changes in behavior, increased susceptibility to disease, or re-duced ability to produce healthy young. Since lab animals lead much shorterlives than humans, it is possible to study effects on life span and reproductionwithout having to wait decades for the results.
In the case of trichloroethylene, chronic exposure has caused cancer as well as damage to the liver, kidneys, and central nervous system of laboratory ani-mals. Whether trichloroethylene causes cancer in humans is still uncertain.
Limited data are available on humans who have used trichloroethylene in poorlyventilated areas. These people have suffered from dizziness, headaches, slowedreaction time, sleepiness, and facial numbness. Data on the concentrations caus-ing health effects such as these are used by the government in setting standardsfor acceptable chronic exposure to trichloroethylene through water, air, andother sources.
A S S E S S I N G T O X I C R I S K : S T U D E N T E D I T I O N S E C T I O N 1 : U N D E R S T A N D I N G T O X I C R I S K C O N C L U S I O NThis chapter describes the process of measuring how a chemical affects labora-tory animals such as rats. You may be wondering how data from these dose/response experiments can be used in the real world. For example, suppose thatscientists have determined that rats tend to develop liver disease when exposedto a certain concentration of trichloroethylene in their daily diets. How can thegovernment use this information in deciding the maximum concentration toallow in human drinking water? Toxicity experiments provide the basis for government regulations that specify what concentrations of certain chemicals are allowed in human food,drinking water, drugs, and cosmetics. The next chapter explains how thisprocess occurs, starting with laboratory data and ending with regulationsabout chemical use.
F O R D I S C U S S I O N◗ What do you think that Paracelsus meant when he wrote that the right dose differentiates a poison from a remedy? Can you think of a substancethat is good for you at one dose and poisonous at another? ◗ Why might it be useful to know the LD50 for a chemical? How might ◗ If a compound is shown to be practically nontoxic in a dose/response bio- assay, can you conclude that this compound will have no toxic effects onliving things? What other sorts of tests might be useful in helping you tomake this decision? N A T I O N A L S C I E N C E T E A C H E R S A S S O C I A T I O N C H A P T E R 1 : T H E D O S E M A K E S T H E P O I S O N Name_____________________________ Date_________________ Based on the LD50 for caffeine (see Table 1.1), how many cups of coffee would you estimate that itwould take to kill an average human of your size (assuming that humans respond in the same way asrats to this compound)? You can calculate this using the steps below: 2. Calculate the average lethal dose for a human your size: ____ mg/kg × ____ kg = ____ mg caffeineLD50 your 3. Assuming that each cup of coffee contains 90 mg caffeine, calculate how many cups it would take to kill an average person about your size: ____ mg caffeine ÷ 90 mg/cup = ____ cups of coffee A. Take a look at the number you calculated in Step 3. If you were to drink one cup of coffee per day for this number of days, would you be likely to die from an overdose of caffeine? Why or why not? B. If you could drink exactly the number of cups of coffee you calculated in Step 3 all at one sitting, would you be guaranteed to die? Why or why not? C. What is the most important assumption that we make when we use LD50s to estimate lethal A S S E S S I N G T O X I C R I S K : S T U D E N T E D I T I O N



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