Beginning in the late 1940s, when Dr. Hueper established an Environ- mental Cancer Section at the NCI, and continuing to this day, a major program of carcinogen identification using animal tests has been con- ducted at the National Institutes of Health (NIH). At the present time most of this testing is conducted under the auspices of a government- wide activity called the National Toxicology Program (NTP) centered at another NIH unit, the National Institutes of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina. Several hundred chemicals have been tested for carcinogenicity by the NTP.
The NTP and other federal health and regulatory agencies also spon- sor epidemiology studies and other investigations into the underlying chemical and biological mechanisms by which some chemicals trans- form normal cells into malignant ones. In addition to government- supported work, there is substantial industry-sponsored testing and research of the same type, some of it performed because of regula- tory requirements. The field of chemical carcinogenesis is a vast sci- entific enterprise, not only in the United States, but throughout the world.
One important part of this vast enterprise is the International Agency for Research on Cancer (IARC), a part of the World Health Organization, headquartered in Lyon, France. One of IARC’s many activities involves convening meetings of scientific experts from across the world to examine published scientific work relating to the carcino- genicity of various chemicals. The IARC periodically publishes the results from the deliberations of these working groups. The agency
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163 Table 6.1 Some of the 95 chemicals and occupational exposures currently listed by IARC as carcinogenic to humans
Note that in many cases data on cancer rates were collected under exposure conditions that no longer exist.
Some occupational exposures
Boot and shoe manufacture (certain exposures) Furniture manufacture (wood dusts)
Nickel refining
Rubber industry (certain occupations)
Underground hematite mining, when radon exposure exists Some chemicals
Aflatoxins
Arsenic and arsenic compounds Asbestos (when inhaled)
Chromium [VI] compounds (when inhaled) Benzene
Diethylstilbestrol (DES)
2-Naphthylamine, benzidine (starting materials for manufacture of certain dyes)
Vinyl chloride (starting material for PVC plastic manufacture) Mustard gas
Some chemical mixtures Tobacco smoke
Smokeless tobacco products Soots, tars, mineral oilsa Wood dust
aMineral oils now in commercial production generally do not have the PAH content they had at the time the evidence of carcinogenicity was gathered.
also categorizes chemicals based on the nature and extent of available scientific evidence concerning their carcinogenic activity. Evidence is labelled as “sufficient,” “limited,” or “inadequate,” and the reviewed chemicals are grouped into these categories; distinctions are made between evidence based on epidemiology studies and that based on studies in laboratory animals.
In Table6.1are listed some of the chemicals and occupational set- tings IARC has categorized as carcinogenic to humans – the data from
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all the available epidemiology studies were considered sufficient by the expert groups to conclude that a causal relationship exists between exposure to the chemical or occupational setting and some form of human cancer.
Several comments should be made on the contents of Table 6.1.
First, it is not complete; IARC now lists a total of 95 chemicals, chemical mixtures, and chemical processes as carcinogenic to humans;
the agency lists another several dozen or so as having limited evi- dence of human carcinogenicity. Second, occupational exposures are listed instead of individual chemicals for those cases in which sev- eral chemicals may be involved in the exposure, and it is not clear which are responsible for the cancer excesses observed in the work- ers studied. Third, the listed chemicals and occupational exposures have been demonstrated to be human carcinogens only for the spe- cific groups of individuals upon whom observations were made by epidemiologists; whether they increase cancer risk for other individu- als exposed under quite different conditions is a separate question, to be treated later in this chapter and in the chapters on risk assessment.
Finally, it should be emphasized that there are many additional ani- mal carcinogens listed by IARC that may also pose a carcinogenic risk to humans, but for which sufficient epidemiology data have not been collected; keep in mind that a chemical can be demonstrated to be a human carcinogen only if an opportunity exists to study it in exposed humans in a systematic way, and such opportunities are not always available.
How evidence becomes “sufficient” to establish causation is a major topic for discussion in the rest of this chapter, as is the relationship between animal findings and human risk.
The accumulating evidence that carcinogenesis is a multistage pro- cess, and that different factors or substances may affect the several transitions a cell has to undergo to arrive at a malignant state, would seem to make obsolete any simple ideas about a “cause” of cancer. So, what does it mean, exactly, when the WHO’s International Agency for Research on Cancer lists smoking as a cause of lung cancer, or the EPA lists benzene as a cause of leukemia? To tackle these questions, and prepare for the coming journey through the world of risk assessment, we need to provide a more systematic and critical look at the two areas of science – cancer epidemiology and experimental carcinogenesis – from which emerges the evidence we use to label various substances as carcinogens.
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Causation and prevention – how does epidemiology help?
Here is a definition of epidemiology that is as good as I have found:
Epidemiology is the study of the distribution and determinants of health- related states or events in specified populations, and the application of this study to the control of health problems.
First, note that epidemiology is by no means limited to the study of cancer, but is used to understand many types of infectious and non- infectious diseases. It is also, as is clear from this definition, not lim- ited to unhealthy states, but includes the study of the determinants of good health. It is also concerned withpopulations, not individuals, and so does not involve the same methods and approaches used by physicians in diagnosing medical conditions, and even their possible causes, in individual patients. It is focused on populations, and results from epidemiology studies pertain only to populations. So, if an epi- demiologist claims that smoking two packs of cigarettes each day for forty years causes a tenfold increase in the chance of developing lung cancer by age 55, he or she is referring to an increased risk in a popu- lation of smokers, and is saying little about any specific individual in that population.
What good is such information? Well, it is critical, essential even, if we wish to improve the public health by preventing disease. The last phrase of the definition makes this point, and it is not an empty tag line. If epidemiologists can determine which populations are most affected by certain disease states, and then do some detective work to figure out how those populations differ from others that suffer less disease, then they have a chance of identifying the conditions that contribute to that disease state. Once epidemiologists have made this determination, public health experts or regulators can begin to work on ways to reduce the presence of the responsible conditions, be they certain chemical exposures, infectious agents, lifestyle factors, or physical phenomena such as radiation. Epidemiology is the key to population-based preventive medicine.
Of course individual people can, for causes under their personal control, also benefit from the results of epidemiology studies; even though epidemiology results apply to populations, individuals at least have an increasedchanceof benefiting by avoiding the substances or factors identified as causes of disease, especially when, as in the case of smoking, the population risk from the causative agent is unusually
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large. Individuals would be well advised to avoid smoking – they will hugely increase their odds of avoiding the many smoking-related dis- eases if they do so. As a generalization, using epidemiology results to fashion personal behavior is most useful, most likely to pay off, for causes the epidemiologists have identified as greatly increasing risks – smoking, excessive alcohol consumption, diets high in satu- rated fat, driving without a seat belt, and a few others. As epidemiolo- gists begin to report on small and even mid-sized risks, the certainty of their findings declines and the benefits of individual action become less predictable.
It is no secret that epidemiologists have a difficult time coming up with conclusive results – everyone is familiar with the “health advice-of-the-month” syndrome, wherein what epidemiologists said was good for you last month is, according to the latest study, now proven to cause some debilitating disease. Although epidemiologists and those who try to report epidemiology results are often ineffec- tive at describing for the public exactly what various studies tell us, it is through a look at the nature of the science itself, and the limits against which it is working, that the fundamental reasons for confu- sion, apparent or real contradiction, and controversy are to be under- stood. As elements of the science and its methods of study are set out in the following, its limits will become evident. We would like to know for sure whether certain substances to which we may be exposed can cause disease, especially if the disease is cancer, but the only means we have available to look at causes, epidemiological studies, cannot usu- ally get us to a “for sure” answer without a long and difficult scientific struggle.
Describing the world of cancer
In the beginning, before there is analysis, there must be accurate description. How much cancer is there, and how do rates of occurrence vary geographically, and between sexes, and with age? How do rates of different types of cancer vary over time, and what happens to the rates that occur in specific groups of people when they move from one geographic location to another? Information describing these types of differences and trends – which can be compiled with accuracy only when cancer registry information is reliable – are enormously bene- ficial in providing clues to the causes of cancer. The statistical data presented in Chapter5arose from these types of studies.
167 Here it should be emphasized that two types of cancer registry infor- mation are available, and afford somewhat different kinds of under- standing. The easiest information to compile is that pertaining to death rates, and its accuracy depends upon reliable medical diagnoses of cause of death and the careful recording of that information. Cancer death rates are, however, not the best types of data for getting to the issue of causation. Death rates reflect both incidence of the disease (how much cancer occurs) and the results of medical interventions.
Incidence data are not influenced by the effects of treatment and are more useful if the goal of the epidemiologist is to gain some under- standing of cause.
It is easy to imagine that incidence data – how many new cases of specific types of cancer occur in a given population over some specified period of time – are more difficult to come by, and it is only in recent years that reliable incidence data have been available. In many coun- tries they are still not readily available. In any case, epidemiologists need to worry about differences in incidence if they are to uncover underlying causes.
Descriptive epidemiology is, however, only the beginning, because it cannot provide significant information regarding specific causes or determinants of cancer. It has been ascertained, for example, through a series of careful descriptive studies, that, after a couple of genera- tions, Japanese immigrants to California exhibited changes in their rates of stomach cancer (declines) and breast cancer (increases) that brought them closer to those found in native Californians. This type of information is profoundly important in establishing that environment is a highly significant influence on cancer risk. It reveals little, how- ever, about the possible underlying causes of these changes, and there- fore little of direct public health benefit. Do we recommend, from the results of such descriptive studies, that Japanese who wish to reduce their risk of contracting stomach cancer should move to California?
Obviously not. What should follow from such observations is more study of the specific environmental factors – certain dietary habits, perhaps – that result in the excess risk of stomach cancer that is seen in Japan.
There is a striking relationship between the levels of meat consump- tion in different countries and the rates of colon cancers in those coun- tries. But does that observation alone establish that meat consumption is causative? Is this type of information, of itself, a sufficient basis for public health authorities to recommend that the citizens of high risk countries such as New Zealand and the United States, for example,
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reduce their meat consumption to something like the levels in Japan and Finland, both very low risk countries? The answer – this type of descriptive data is not difficult to acquire – is almost certainly no.
It would be a mistake to interpret information of this type as estab- lishing that meat consumption is a significant cause or contributor to colon cancer risk. There are several reasons why such a conclusion is fallacious.
First, there is no way to know whether, within each country, those groups of people who eat more meat exhibit greater rates of colon cancer than those who eat less or even no meat. Data concerning total or average meat consumption provide no clues about how that consumption is distributed among members of the population; more- over, the distribution patterns in different countries are surely variable.
The data are also uninformative on the question of duration of meat consumption – they do not reveal whether rates rise with increasing duration of meat intake.
Perhaps meat consumption is related to some other factor and it is that other factor that is the real culprit. Do heavy meat eaters consume more alcohol than those who consume less? Do heavy meat eaters con- sume less fiber? Even if the latter were true, and we were to construct a figure relating fiber intake to colon cancer, and found that coun- try rates went up as fiber intake declined, we would still fall short of demonstrating causal links between decreased fiber consumption and increased colon cancer rates.
These types of data are too often over-interpreted, and taken to provide more insight than is possible. The well-trained epidemiologist understands the limits, knows that, at most, such data only suggest where to look for more telling information. Descriptive studies are exceedingly important clues to the causation problem, but are no more than that.
Other clues arise from what are called case-reports. An English physician, John Hutchinson, reported, back in 1887, on unusual skin growths, including cancers, on individuals given Fowler’s Solution (arsenic oxide) as a medicine. In 1970 Arthur Herbst of Harvard University identified seven young women who, over the course of one year, were diagnosed with a form of vaginal cancer that was extremely rare for their age group, and he suspected and reported that the use of the synthetic estrogen diethylstilbestrol (DES) by their mothers during pregnancy was possibly responsible. Unusual medical conditions such as these are often reported in medical journals, and the physicians reporting them may or may not have a guess about their cause. If the condition is not cancer or some other disease that typically requires a
169 long period to develop, and the physician notes some common expo- sures (a particular medicine, say, or some occupational exposure) that are in the patients’ recent history, his or her guess about the cause may be worth further study. Also, if the cancer is an extremely rare one and common exposures, even if they occurred many years in the past, are readily discernible, the physician’s guess may be a reasonable one.
If, however, the cancers are not extremely rare, the physician’s guess about cause is likely to be a poor one, even if he or she thinks that all the patients experienced some common exposure, even an expo- sure that is unusual. Case-reports, or even reports of a series of cancer cases, even if they are rare cancers or if the cases experienced com- mon and unusual exposures, are almost always insufficient to establish causation. At most, they can provide important clues for follow-up studies.
From descriptive to analytical studies
The problem with the case-report approach is that there is no com- parison group, and no control subjects. Cancers of different types occur at different rates within a population, and these rates also vary with age, geographic location, and often with sex, race, and ethnicity.
Sometimes, in certain groups of people, rates are in excess of what is normally expected, because those people are exposed to certain factors that increase cancer risk. If such factors are to be identified, the epidemiologist must be able to demonstrate that cancer rates in the exposed population are, indeed, in excess of what is normally expected – a comparison group, unexposed to the factor, is the source of information on what is normal. A demonstration that a group of individuals experiencing excess cancer rates is exposed to some fac- tor and that the control group is not so exposed is, for a number of reasons we shall get to, insufficient to establish that the factor is the cause, but such a demonstration is the starting point – the essential first step.
A demonstration of this nature is said to establish an association between the factor and the excess cancers. Two events – in this case the factor and the excess cancers – are said to be associated when they occur together more frequently than they should ifchance alone were operating. We need to turn to statisticians to figure out whether the odds are greater than those associated with a chance occurrence.
Association is not causation, but demonstrating that an association exists gets the epidemiologist part of the way to an answer.
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Before describing the path that gets us the rest of the way to an answer, we shall describe the kinds of studies necessary to determine whether associations exist. Because the epidemiologist is attempting to understand effects in human populations, he or she cannot undertake experiments. Experiments are reserved for the laboratory, where it is possible to deliberately expose a group of animals (or cells in culture) to a suspect agent, and to compare the responses of animals in that group with those in a group of unexposed animals. In the lab setting, if the experiment is well performed, the exposed and unexposed animals are, in every other respect – genetic background, diet, environment – identical. So, in such circumstances, demonstration that the exposed group develops more neoplasms of a certain type than the unexposed group, not only establishes an association, but also provides strong evidence for causation. Obviously, for ethical reasons, we could never conduct such an experiment in human populations.
Note also that, even if some evil epidemiologists could undertake such an experiment in humans, there is virtually no way two human populations could be assembled and matched in the way lab animal populations can be matched, so that causation would remain difficult for the epidemiologist to establish. This “matching” problem begins to explain why there is much distance to travel even after an association is demonstrated.
One other aspect of epidemiological science should be mentioned before we examine the types of studies that can ethically be undertaken to get us on the road to a determination of causation factors in cancer.
There is a branch of the science in which human “experiments” are, in fact, undertaken. Such experiments are known as clinical trials, and most are devoted to studying the potential benefits of drugs, other medical therapies, and certain dietary regimens. Such trials are entered only after it is established to the extent possible, through experiments in animals, that the drug or other therapy will do no harm to the study subjects. Often, unexpected “side effects” will be noted during such trials, and information on such effects is critical to understanding the drug’s or therapy’s “risk–benefit” profile, but such trials cannot be entered unless there is good reason to believe harm will not occur. We treat this subject more fully in Chapter8.
Epidemiologists also conduct planned community trials to learn about the benefits of various nutritional programs or other efforts to improve public health. Again, such experiments with human pop- ulations are permitted only if there is a high degree of certainty that no-one will be harmed.