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Medicine for the Layman Environment and Disease 

Clinical Center of the National Institutes of Health 30oct98


Environment and Life Expectancy Chemicals and Human Disease Cancer and Chemicals
Epidemiology Laboratory Animal Studies Criticism of Animal Tests
Questions and Answers


Americans continue to demand a greater role in deciding issues that affect their health. Increased health awareness and the convincing evidence linking lifestyle, risk factors, and specific diseases have accelerated our need to know.

The Clinical Center, recognizing the importance of providing information to facilitate intelligent decisions on health issues, created a unique lecture series featuring distinguished physician-scientists working at the frontiers of biomedical research at the National Institutes of Health (NIH).

The series-Medicine for the Layman-has provided an opportunity for thousands of people to learn more about how their bodies work and what they can do to maintain or improve their health.

This publication is one of several adapted from the lecture series. It is our sincere hope that you will find this material interesting and enlightening.

Mortimer B. Lipsett, M.D.
Director, The Clinical Center
National Institutes of Health

Presented by David P. Rall, M.D., Ph.D. Director, National Institute of Environmental Health Sciences, and Director, National Toxicology Program 1971-1990

The Medicine for the Layman series is published by the Clinical Center of the National Institutes of Health. For more information write to: Office of Clinical Reports and Inquiries, Building 10, Room 5C305, NIH, Bethesda, MD 20205.


Environment and Life Expectancy

There has been a great increase in life expectancy since 1900. Our life spans today extend well into the 70s. Many things have happened since 1900 to cause this very dramatic increase in life expectancy. First is an increased standard of living. We eat better, we are better housed, and we are warmer. Second, there is better basic sanitation. We have sewers that work and daily trash removal. Perhaps the biggest single change is clean water. Death rates in various large metropolitan cities decreased dramatically when clean water was brought into those cities from a central source. Clean water is one of the major elements of the healthier environment we have today.

Finally, we are able to control many acute infectious diseases that primarily affect young people. In fact, most of the increased life expectancy is a result of prevention of deaths in children and young adults. Children no longer die of infant diarrhea and a variety of other diseases that exacted a great toll in the past.

Now we live in a predominantly middle-aged society that rapidly is becoming a society primarily composed of older people. An individual's life expectancy after the age of 50 has remained fairly constant since 1900. However, the pattern of deaths has changed. We are dying of different things. Death rates for such pulmonary diseases as tuberculosis and pneumonia have decreased. Deaths from cardiovascular disease have increased in the past, but appear to be leveling off or decreasing. Yet cancer death rates have risen steadily and still seem to be increasing.

As a result of these different patterns of life and death we have to contend with different diseases today. Now we are dealing unsuccessfully with such chronic longterm diseases as cancer, heart disease, kidney disease, and neurological diseases. We do not understand the causes of these diseases; there appear to be many factors involved. One of the prominent factors in the causation of many of these diseases may be chemicals.


Chemicals and Human Disease

We know that chemicals can cause many human diseases. l think that this concept is best established with tobacco smoking, the major cause of lung cancer. Another major cause of disease is the compound asbestos. It causes mesothelioma, (an unusual tumor of the linings of the chest and abdominal cavity), lung cancer, and increases in gastrointestinal cancer as well as asbestosis, a chronic fibrous disease of the lung. Since we use 600,000 tons of asbestos every year in the United States, this compound presents a major health problem.

Recently, we discovered a number of chemicals that cause sterility, particularly in men. Within the last three or four years, we have established that two pesticides, kepone and dibromochloropropane, cause sterility in men. Currently, we are investigating new evidence that benzene, a major industrial chemical and a component of unleaded high-test gasoline, also can cause sterility.


In addition, the experiences of workers at a kepone-producing plant in Hopewell, Virginia, have provided dramatic evidence that chemicals can cause neurological diseases. Kepone inhaled by workers may have become embedded in their brains causing nervous tremors, twitching and flickering eyes.

These are just a few examples of the problems created by the everincreasing production of synthetic organic chemicals. In 1918, about 10 million pounds of synthetic organic chemicals were produced, used, and disposed of in this country. By 1936, production was up to 860 million pounds a year. The numbers have increased dramatically over the years: 1941, 2 billion; 1944, 37 billion; 1947, 38 billion; 1961, 100 billion; and 1979, 300 billion pounds of synthetic organic chemicals were made, used and disposed of in the United States. This figure amounts to nearly 1,700 pounds of chemicals for every man, woman, and child in the United States.

We have been exposed to a variety of these chemicals. The following examples illustrate the pervasiveness of this exposure. In the late 1960s, when DDT was used extensively, blood and urine levels of this chemical were high in the people tested. These levels-now are decreasing, nearly 10 years after use of the chemical was banned. Pentachlorophenol is a wood preservative used around boatyards, on poles, and on wood that has contact with the ground. Exposure to pentachlorophenol is particularly dangerous because commercial samples of this preservative contain traces of the dioxins, which can be lethal. In the early 1970s, some residents of Hawaii, exposed to much marine activity and wood preserving, were found to have levels of pentachlorophenol in their urine. Finally, although the polychlorinated biphenyls, known as PCBs, virtually have been banned, our body levels of the chemical remain constant.

Furthermore, enormous amounts of PCBs are in the environment. PCBs enter the food chain and into human diets primarily through consumption of certain fresh water fish. Infants as well as adults can be exposed to these chemicals. Polychlorinated biphenols can be passed to babies through breast milk.



Cancer and Chemicals

There is increasing evidence that many uncontrolled chronic diseases are caused in part by exposure to environmental chemicals. Discussions of chronic diseases caused by chemicals usually concentrate on cancer. Cancer is an important disease; approximately 20 percent of all people in the United States die of cancer. We concentrate on cancer because we know much more about it than any other chronic disease. We have better records about cancer; it is better diagnosed and followed than many other equally important chronic diseases.

Basically, there are two ways to determine the causes of cancer: studying people or studying laboratory animals. Both techniques are important but both techniques have strengths and weaknesses. It is important to understand these strengths, weaknesses, and limitations.



Epidemiology, or the study of the occurrence of disease in people, is the most common method of determining a cause of cancer. This technique is easily accepted and certainly the most easily understood. Associating exposure to a chemical with a large number of people either dead or ill with an identified disease often can be very simple and straightforward. In fact, most health regulations today are based on epidemiological studies.

Epidemiological studies are very old and have a glorious and grand tradition. The report, in 1775, by Sir Percival Pott of England, that chimney sweeps had a very high incidence of scrotal cancer may have been the first epidemiological study.

However, there are many problems with epidemiology. Usually people do not know the chemicals they have been exposed to and the amount of their exposure. To produce a good epidemiological study it is critical to know chemical exposure and quantity, not only for the workers, but also for consumers of a product. In addition, people find it very difficult to remember the important exposures of 5, 10, or 15 years ago as well as the exposures of today or yesterday.

Another major problem is that this method cannot detect small differences in the rates of common diseases. Although a very large number of people may be affected by a common disease, relatively small differences cannot be picked up by epidemiology. For example, it would be very difficult to determine epidemiologically if a chemical increased the rate of a common disease.

Perhaps the most significant problem is that epidemiology is entirely an after-the-fact science. Diseases can be related to causes only after people have experienced exposures of sufficient intensity and duration to produce illness and death.

This delay is less important when the effect, such as an adverse drug reaction, happens very rapidly. However, chronic diseases, particularly cancer, have a latent, or silent, period of decades. Most cancers do not develop until 20 or 30 years after exposure has occurred. Therefore, it may be necessary for an entire generation of people to be exposed to a chemical before epidemiological studies can prove that a particular compound does cause cancer or some other chronic disease.



Laboratory Animal Studies

Use of laboratory animal studies as a method to identify carcinogens is only 50 or 60 years old. These studies have been much improved in the last few years and attempts to examine their reliability and predictability have increased over the last 5 or 10 years. During this time scientists have refined the methodology of laboratory animal studies. Today these studies are better constructed, performed, and evaluated than they were 10 years ago. A good animal study is a very complex study. It is not the simple observation of a dozen rats in a shoebox.

The critical question to ask about a laboratory animal study is its predictability. Do results of laboratory animal studies predict for those effects in a human population? The International Agency for Research on Cancer, a part of the World Health Organization, assembles expert groups of independent scientists to determine if there is adequate evidence to indicate a chemical is carcinogenic. This agency has published a list of about 20 chemicals that are carcinogenic in man. Nearly all of the chemicals on this list also are carcinogenic in laboratory animals. Two exceptions are arsenic compounds and benzene. However, there is new evidence that strongly suggests that benzene causes leukemia in rats and mice in the same way it causes leukemia in man. In addition, arsenic may well be a cocarcinogen, at least qualitatively. This list strongly suggests that chemicals that are carcinogenic in man will have been found to be carcinogenic in animals.

Another important issue focuses on the amount of a chemical needed to cause cancer. Are the amounts or doses of chemicals that cause cancer in man the same as those that cause cancer in the laboratory animals?

Several years ago, a study committee of the National Academy of Sciences' National Research Council carefully reviewed this problem. The committee compared the available evidence for amounts of chemicals needed to cause human cancer with laboratory data about cancer in the animal species most sensitive to a particular chemical. Three out of the six situations studied showed a direct relationship between the amount of chemical exposure and cancer in animals and man. For both the dye benzidine and chlornaphazine, a drug no longer in use, the amount of the chemical causing cancer in occupationally exposed people was the same as the amount that caused cancer in laboratory animals.

Although it is very difficult to encourage a mouse to smoke cigarettes and apparently not at all difficult to persuade people to smoke, there seems to be a very close relationship between the number of cigarettes smoked and the production of cancer in both people and animals.

In three other test situations, the relationship was not as direct. The most sensitive laboratory species was ten times more susceptible than man to cancer caused by a fungal toxin (aflatoxin) of peanuts, corn, and other vegetables. Although animals appear to be more sensitive to diethylstilbestrol (DES), the human population is still at risk for this chemical. In fact, if in the future more diethylstilbestrol-caused cancer is observed in people, carcinogenicity in animals and man will be closely related. It is possible that the carcinogenicity of diethylstilbestrol could have been predicted. After the chemical was observed to be carcinogenic in young women whose mothers took DES, animal studies clearly showed that DES produced exactly the same cancer in the offspring of mice. The same may be true for vinyl chloride. Again, the animals seem to be more sensitive, but the worker population exposed to vinyl chloride is still very much at risk.

These examples show that animal studies predict carcinogenicity and that the predication of disease is fairly accurate. Animal studies are not perfect but they do have merit. l believe that with increasing frequency we will encounter situations like DES in which animal studies could have predicted carcinogenicity in man. Vinyl chloride was discovered to cause cancer in animal studies before like effects were observed in factory workers in Louisville. Aflatoxins were observed to cause cancer first in trout, then in laboratory animals, and finally in human populations by use of epidemiological studies in Africa. Another example is bischloromethyl ether, a chemical by-product of an open pot manufacturing process.

Although an epidemic of lung cancer had been noticed in a small factory, laboratory animal tests pinpointing the single chemical bischloromethyl ether as the cause of lung cancer were required in order to close the manufacturing process and prevent further worker exposure to the dangerous chemical. As a result of this decreased exposure, the incidence of lung cancer decreased.


Criticism of Animal Tests

There are problems in understanding and using laboratory animal tests. Much of the public and, in fact, a fair segment of the scientific community are reluctant to put faith in laboratory animal tests. These people are uncomfortable with the relationship between men and mice. Scientists often debate the value and meaning of certain tests. It is important to scientific study that theories are tested and retested and not prematurely accepted. However, I think the relationships and the concepts that laboratory animals predict for man are quite good. There is empirical evidence from a variety of studies that animals do predict for man, not only for cancer, but for other forms and quantities of toxicity.

Mammalian species, ranging from tiny mice to enormous elephants, are very similar in their biological function, physiology, and biochemistry. Such extensive similarities have permitted us to learn much of what we know about human physiology and biochemistry by the convenient and effective study of laboratory animals.

Many people who are unfamiliar with this type of research question the need to administer large doses of chemicals to the animals in laboratory tests. The amount of chemical used is related primarily to what we call the statistical power of the animal tests. It is extremely difficult to detect anything less than a very strong carcinogen unless researchers use either an enormous number of animals, hundreds of thousands, or larger doses and fewer animals. Negative test results from small numbers of animals simply mean that a chemical is not an extremely powerful cancercausing agent or carcinogen.

Animals are not unlike humans; nearly all strains have some incidence of cancer in the general population. This fact further complicates research results. After an animal test is designed and chemicals are administered to the animals, the scientists must decide which of the resulting cancers were caused by the chemical and which might have been present as the normal incidence. This decision poses severe statistical problems. The chance of detecting a two-fold incidence of cancer using 50 rats is just 2 in 1,000, an almost infinitesimal chance of detecting a cancercausing agent. By doubling the number of animals to 100 rats, there still is only a 2 in 100 chance of doubling the background rate of cancer. Because of economics and resources it is impossible to use thousands and thousands of animals. The only other alternative is to use larger and larger doses of the chemical being studied. These doses are not lifethreatening per se; they do not cause other toxicities in the animal population, but are simply larger doses.

Although there are other reasons for using large doses, such as the fact that animals excrete chemicals faster, the main reason large doses are necessary and valid is due to the lack of statistical power, of a test using only 50 or even fewer animals in each experiment.

I have pointed out that the relationship between disease in man and ir animals is good, but it certainly is not perfect. This imperfect relationship often is a major criticism of laboratory animal tests. I do not believe that this is a valid criticism since we live in an imperfect world We have learned to deal with such imperfection. For example, all of us listen to the weather report and generally we believe it. Most of the time the report is correct, but some of th time it is not. However, we would much rather have the weather forecast than have nothing at all.

Many people have expressed the belief that everything causes cancer, that the discovery of a new carcinogen is "nothing new." There are two reasons for this pervasive feeling. The most important reason is that cancer testing in laboratory animals began in earnest only about 5 or 10 years ago. Since it takes about five years to develop a full test, during the past three or four years we have learned the results of the first largescale testing of potentially cancercausing chemicals in our environment. We are seeing a large number of positive reports. However, not every chemical causes cancer. In the initial large-scale National Cancer Institute study, scientists selected to study 120 compounds which were suspected of being carcinogenic. Of these 120 specifically chosen (not randomly chosen) compounds, less than 10 percent were found to cause cancer.

In addition to using animals for studying cancer, scientists at the National Institute of Environmental Health Sciences and other institutions are beginning to develop animal tests for other chronic diseases. However, these tests are not as well developed as those for cancer. It will take a number of years before we can discuss these tests with the quantity of evidence that we have for cancer tests.

I believe that animal tests should be used to study chemicals to see if they do cause cancer or other chronic diseases. If the chemicals do cause diseases, we need to restrict or control their use. Restriction does not always mean banning a chemical. However, it does mean reducing exposure to minimize the risk of developing disease. If we do that, we can control some of these serious chronic diseases. Such control is an enormous task because of the huge numbers of scientific, technical, logistical, social and economic problems that must be addressed and solved. Nevertheless, as a general principle, I suggest that we enter into a partnership with laboratory animals and work to control chronic diseases.


Questions and Answers

Q. What percent of the 1,700 pounds of chemicals that are manufactured annually for each of us is composed of carcinogens?

A. We simply do not know. There are 50,000 chemicals in commercial production. It is estimated that about 10,000 are in significant commercial production and perhaps 2,000 present significant exposure levels. We do not know what fraction of those have been adequately tested, but certainly it is not much more than 10 to 30 percent.

We are starting a literature study in an attempt to estimate how well these widely used compounds have been tested. This study probably will require two or three years to complete, but when completed, it should provide the answer to your question.

Q. About five years ago there was great concern that DES-exposed daughters would develop cancer. What are the chances that this disease will develop in 10 or 20 years in a DES-exposed daughter who does not have cancer now?

A. An extraordinarily large number of women were exposed to DES. Although a fair number of their daughers did develop cancer, the actual risk to any one person does not seem very great at all, perhaps one in thousands.

Q. Would you mention some of the other chronic diseases that may be caused by chemicals?

A. There is some evidence that certain chronic kidney diseases have a chemical origin. Chronic glomerulonephritis, a major social problem in the United States today, may occur more frequently if there has been exposure to a volatile solvent just before the initiating infection. Many liver diseases are associated with chemicals. For example, vinyl chloride causes a very severe chronic liver disease.

Chloracne is one of a number of chronic skin diseases related to chemical exposure. In addition to pulmonary problems caused by cigarette smoking, many of the pulmonary fibroses are caused by inhalation of toxic chemicals. A final example is the association of a type of diabetes with exposure to a pesticide.

Q. Have mental or emotional disorders been linked to chemical exposure?

A. Not that I know of.

Q. Do you think that screening techniques like the Ames Test will be effective in the future?

A. I think they will be terribly important in the future. Many investigators believe that most cancers originate in a mutation or change in a cell's basic genetic material. The mutation causes the genetic material, also known as DNA, to give a wrong signal to the next generation cell. Most chemical carcinogens cause such mutations or changes in DNA. During the last 5 to 10 years, scientists have developed a number of very simple tests using mammalian cells grown in tissue culture which can very rapidly and cheaply identify these mutations. "Informal" studies have shown that there is quite a good correlation rate between the ability to produce mutations in these tests and the ability to cause cancer in animals. At the moment, however, these tests are very new. They have not been validated. We do not know if they are reproducible and predictable. Under the National Toxicology Program, hundreds of chemicals will be tested for mutational activity to determine if the Ames Test is reproducible and if it predicts for carcinogenicity in laboratory animals or in man. Screening techniques like the Ames Test will make an enormous difference in the future; but it is a little premature to use them now.

Q. After asbestos was identified as a carcinogen in people, asbestos ceiling tiles were removed from many school buildings. Should i replace the asbestos roof on my house?

A. Although asbestos is a nasty fiber, sheets of flooring or roofing material containing asbestos are considered safe since the fibers are embedded in cement or plastic.

Asbestos is considered very dangerous when the material hangs loose and dust can be produced when the asbestos is hit or manipulated.

Q. Have asbestos mines been closed?

A. No, asbestos continues to be mined and sold.

Q. Who is alerting the public to the dangers of these chemicals that are discovered to be carcinogenic?

A. The National Institute of Environmental Health Sciences and the National Cancer Institute have some public awareness programs.

In addition, the Environml Defense Fund and the No Resources Defense Coun very aggressive programs

Q. Do you think it is ina eat tuna fish since it coul concentration of whateve are found in the water?

A. It does not seem like problem. There was the rr cury scare in the early 19 ever, based on current knee the levels in tuna fish essl safe. l think tuna fish prot about as good a food as <

Q. Do you have any opir calcium propionate or ant other preservatives found?

A. Not specifically. Most atives have been tested al that were inadequately tee being retested.

Q. Is cyclophosphamide the treatment of some fon breast cancer?

A. Yes. And it is a very e anti-cancer drug. However, a carcinogen.

Q. Are asbestos plates u pots to prevent food from over or burning dangerous?

A. I think that most scif used exactly the same as pads on their Bunsen but is relatively little fiber rele those pads. Probably it is not to use them, but they type of major hazard I we about.

In addition, the Environmental Defense Fund and the National Resources Defense Council have very aggressive programs.

Q. Do you think it is inadvisable to eat tuna fish since it could contain a concentration of whatever chemicals are found in the water?

A. It does not seem like that is a problem. There was the methyl mercury scare in the early 1970s; however, based on current knowledge, the levels in tuna fish essentially are safe. l think tuna fish probably is about as good a food as any.

Q. Do you have any opinion about calcium propionate or any of the other preservatives found in foods?

A. Not specifically. Most preservatives have been tested and those that were inadequately tested are being retested.

Q. Is cyclophosphamide used in the treatment of some forms of breast cancer?

A. Yes. And it is a very effective anti-cancer drug. However, it also is a carcinogen.

Q. Are asbestos plates used under pots to prevent food from bubbling over or burning dangerous?

A. I think that most scientists have used exactly the same asbestos pads on their Bunsen burners. There is relatively little fiber release from those pads. Probably it is prudent not to use them, but they are not the type of major hazard I would worry about.

Q. What is happening to towns like Hopewell, Virginia? Do they continue to develop their chemical industry? How can we be protected from incidences like those that happened in Hopewell and Love Canal?

A. Hopewell is a chemical industry town and apparently is growing. The plant that caused the kepone problem has been closed and dismantled as a result of effective legal action.

We simply do not know enough about toxic chemical waste dumps as epitomized by Love Canal. Perhaps _00 chemicals can be found in Love Canal. There is intense Congressional activity to develop legislation to deal with this major problem and clean up these old dumps.

Since new regulations on dumping are much more restrictive, most problems do not develop in the dumps being used today, but primarily involve those older dumps that were used and then forgotten. l believe that toxic chemical waste disposal will remain as one of our major problems for the next three or four years.

Q. There is considerable concern today about the chronic health hazards of radiation. Would you consider chemicals to be an equal health hazard?

A. I do not pretend to be an expert on radiation and I think it is difficult to make that sort of comparison.

Radiation and chemicals are both very serious problems. Radiation is much better controlled in the United States than carcinogenic chemicals.

Consequently, I think that, currently, chemicals may be a much larger problem. But that is a very unscientific estimate.

Q. How large an increase in cancer incidence would be necessary before a chemical could be identified as a problem?

A. Many studies have pointed out the weaknesses of epidemiology. For example, a New York University group conducted a study on breast cancer and users of hair dyes.

In this fairly large study, researchers found a doubling of the incidence of breast cancer among those women using hair dyes who had low natural susceptibility to breast cancer. This finding was barely statistically significant, right at the borderline, yet this relationship could cause literally tens of thousands of additional cases of breast cancer.

In addition, this study only went back 15 years. Based on our knowledge of other carcinogens in the human population, after 15 years we just begin to see the effects of chemical exposure. Unfortunately, that is the best answer I can give to your question.

Q. It is very clear to me that animal studies will have to be used to determine the approximate levels of permissible exposure to a chemical in our environment.

How do we relate the doses used in animal studies and the length of time required for a tumor to develop in animals to the same situations in humans?

Do we know how to translate 143 days in a mouse into years in a human being?

A. You bring up a very good question. Exprapolating from animal studies, a heavy cigarette smoker has a 50/50 chance of developing lung cancer in about 145 years.

The time required to develop a tumor is a surprisingly insensitive way of analyzing research results.

The disparity between a mouse and a man makes us uncomfortable about comparisons, but the empiric evidence suggests that we should not be as uncomfortable as we might intuitively feel.

Q. What suggestions do you have for workers who suspect that working conditions may be impairing their health?

A. Under a provision of the Occupational Safety and Health Act of 1971, workers can ask for a health hazard evaluation from the National Institute for Occupational Safety and Health (NIOSH).

Any worker with concerns about his or her working conditions can contact NIOSH for more detailed instructions for requesting such an evaluation.

Q. Is cigarette smoking more dangerous at particular ages?

Do older people have fewer defenses to protect them from the effects of smoking than someone in their 20's or 30's?

A. Cigarette smoking is basically bad. It is worse if you are pregnant. If an individual starts smoking at age 60 or 70, he or she probably is in good shape because of the time required for a tumor to develop.

Since it might take 30 or 40 years for the tumor to develop, cancer may not be very important to a person 100 years old.

Q. Are there any toxic effects from the production of manmade fibers or their use in clothing?

A. Although it has been observed that we are seeing an increasing amount of sunlight-induced skin cancer because of the light weight and skimpy clothing our society wears, l do not think that the ingredients of our clothing present dangers. The people at greater risk from these artificial fibers are the workers who produce the raw materials, the workers who initially manufacture the fibers, the people who live downstream of the manufacturing plant, and the people who may live near a dump receiving fiber residue.

Once the fibers are locked in place in cloth, they are relatively harmless.

source: http://www.niehs.nih.gov/oc/factsheets/ead/text.htm Last revision: 30 Oct 98

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