[CANCER RESEARCH 48, 1381-1389, March 15, 1988 ......difficult and slow, represents the most logical alternative. This will require long-term major investments in fundamental research

[CANCER RESEARCH 48, 1381-1389, March 15, 1988]

Perspectivesin CancerResearch

Changing Concepts in Cancer Prevention: Limitations and Implications for Future

Research in Environmental Carcinogenesis

John HigginsonInstitute for Health Policy Analysis, Georgetown University Medical Center, Washington, DC 20007

Abstract

While the cause and nature of certain human cancers are known,definitive preventative guidelines still cannot be offered for many typesof tumors. This is partly due to the inherent biostatistical and epidemiolÃ³gica!limitations involved in the identification and interpretation ofcomplex carcinogenic risk factors and potential low-risk hazards.

Two divergent control strategies have emerged: (a) regulatory programs designed to control or eliminate minute quantities of pollutants inthe ambient environment, based on fairly rigid quantitative risk assessment; (ft) a biological research effort to understand the fundamentalbiological mechanisms with the objective of eventually manipulating orintervening in carcinogenesis through chemoprevention or therapy. Apartfrom more intensified effort on certain already recognized causal factors,current research indicates that the eliminatory approach will have littleimpact on the cancer burden and that the mechanistic approach, althoughdifficult and slow, represents the most logical alternative. This willrequire long-term major investments in fundamental research and manpower. This biological approach, however, is largely ignored by the publicand legislative bodies concerned with cancer control strategies, partlydue to lack of formal input to appropriate national bodies by experts inchemical carcinogenesis. Informed scientists have an important role inensuring that the public and legislative bodies are aware of currentscientific views on carcinogenesis and the need to establish priorities inresearch.

False facts are highly injurious to the progress of science, forthey often endure long; but false views, if supported by someevidence, do little harm, for everyone takes a salutary pleasurein proving their falseness.

Charles Darwin in The Descent of Man, Chapter 21

Early studies on the geographical and temporal variations incancer incidence in different countries, communities, and migrants, complemented by analytical epidemiolÃ³gica! investigations on cultural and occupational cancers, led to the view thatmost human cancers have a significant environmental component (1). By deemphasizing the role of hereditary factors, suchstudies have indicated the considerable possibilities of cancerprevention by removal or reduction of exogenous carcinogensin an occupational setting, possibly modification of "life-style"

factors (especially use of tobacco, change in diet), or use ofvaccines, e.g., hepatitis B and liver cancer. Today there is ageneral consensus on the identifiable or probable causes ofmany human cancers and their nature (2-4). In the past, cancercontrol through elimination of carcinogenic factors has beensuccessful for several types of cancers (2-4).

Nonetheless, despite major epidemiolÃ³gica! and laboratoryefforts over the last two decades, specific preventative measurescannot be recommended with any certainty for about 50% ofcancers in males and 70% in females (2-4). Further, the complexity of environmental risk factors has been demonstrated byrecognition of the multistage nature of carcinogenesis (5, 6)

Received 7/10/87; revised 10/16/87; accepted 11/17/87.

and the numerous modulating factors involved in both humansand experimental models.

Accordingly, the intellectually attractive idea that control ofthe many animal carcinogens, mutagens, and promoters (bothman-made and natural) in the ambient environment would alsosignificantly reduce the cancer burden (7) has become widespread and has had considerable political impact, especially inview of the perceived slow progress of cancer therapy. However,the role of such ambient chemical pollution as a major factorin human carcinogenesis is now being critically reevaluated (8).

In 1980, Berenblum (9, 10) described several hypotheticalapproaches to human cancer prevention. These included: theelimination of complete carcinogens; the elimination of possibleinitiators based on laboratory tests, e.g., mutagens, an approachwidely used today by regulatory authorities; and the eliminationof various promoting factors during the long latent period ofcarcinogenesis. In this category, Berenblum clearly includedany type of modulating or enhancing factor involved in carcinogenesis. However, based on current research trends, his conclusion was that the most effective approach in the future wouldbe interference in the carcinogenic process rather than theelimination of "incriminating" factors within the environment.

Although a longtime advocate of the traditional eliminatoryapproach to prevention, I am now convinced that recent progress in biology and carcinogenesis research confirms the essential validity of Berenblum's views, although they are largely

ignored in regulatory policy and public debate. Further, itappears to me that, apart from the application of existingknowledge on the causes of cancer, increasing efforts to reducecancer based only on such methods may have relatively littleimpact in reducing the present burden of cancer due to inherentbiological, statistical, and social limitations.

This paper briefly summarizes some of the scientific arguments for this thesis. It also attempts to analyze the implicationsfor the public policies of the American Association for CancerResearch in advising on the future direction and priorities ofcancer control programs and research strategies.

Role of Epidemiology in Cancer Prevention

Epidemiology has been the major discipline used to testcausal hypotheses in human cancer. Such hypotheses have oftenarisen from chance clinical observation or, less frequently,through systematic investigations in a cultural, occupational,or therapeutic setting or laboratory bioassays. The criteriagoverning such investigations are well known. In general, themull Â¡factorialnature of many cancers and their long inductionperiod require that for a cause(s) to be demonstrable, a reasonable number of persons must be exposed to a carcinogenic riskfactor of some potency for some time. No single criterion canestablish causality, and the evidence must be evaluated as awhole, including biological plausibility (11, 12).

Modern cancer epidemiology is a sophisticated science, notonly relying on traditional ecological and analytical studies (13)

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CONCEPTS IN CANCER PREVENTION

but also using new technologies and concepts developed in thelaboratory to analyze complex carcinogenic risk factors (14,15). However, such studies have well-recognized limitations(11, 12, 16), including: (a) lack of sensitivity; (b) difficulty indiscriminating between several plausible risk factors in complexsituations where none is key or critical; (c) inability to evaluatethe impact of recent exposures; and (d) uncertainties in interpreting "negative" studies or inverse relationships.

Analytical epidemiological studies, even under favorable conditions, usually are insufficiently sensitive to detect cancerincreases or decreases below 1:1000, except for certain raretumors. A "negative study," even with large numbers, will

usually be compatible with a 20% increase in risk (17). Theinterpretation of "negative" or weak associations in epidemio

logical investigations requires considerable scientific judgmentand expertise (18), as illustrated by studies on low-level radiation (19, 20), socioeconomic factors (21, 22), or dietary inconsistencies (23).

Traditionally, primary cancer prevention has been most successful where a discrete and necessary cause, such as tobaccoor a specific chemical exposure, has been identified (2-4).Where carcinogenic risk factors are of considerable magnitude,specific and demonstrable in humans, no serious scientific orsocial problem usually arises in advising on possible preventa-tive strategies through elimination and control, whether thefactor be a discrete chemical or mixture, cultural habit, or virus.In contrast, there is controversy associated with the determination of the significance of low-level potential chemical hazards or the analysis of complex "life-style" and socioeconomic

factors. In such cases, the deficiencies of the epidemiologicalmethod are most apparent.

Evaluation of Small (de Minimis) Potential Cancer Hazards

In a modern industrial state, apart from certain classicaloccupations and specific point sources, exposures to manycarcinogenic chemicals as identified in animal bioassays usuallyoccur at levels below that at which a carcinogenic effect can bedetected by classical epidemiological methods (3, 4, 24). Thus,Hemminki and Vainio (24), in an unique comparative study ofthe levels of potential environmental carcinogens, have calculated that workplace exposures in Finland are usually belowthose at which a detectable effect could be anticipated and thatmost ambient exposures are several orders of magnitude less.

The lack of sensitivity and the inability of the epidemiologicalmethod to measure very low (de minimis) risks which representmatters of great public concern pose problems for regulatorybodies which are required both to reduce carcinogenic environmental risks and to justify the effectiveness of their regulations.Thus, they face ever growing lists of many different types ofbiologically active chemicals in the human environment (bothman-made and natural) which cause or enhance tumor formation in animals but for which the impact of humans cannot bedetected //; tolo or individually by the epidemiolÃ³gica! method.In the United States, the open nature of the regulatory processand the need to avoid the impression of bias has led to pressureto measure numerically such risks by theoretical biomathemat-ical techniques (16, 25-27).

Quantitative Risk Assessment. Quantitative risk assessmentas applied to carcinogens implies the use of selected biomath-

ematical models to calculate the probability of a potentialcancer risk to humans as a result of exposure to a very low levelhazard, usually a chemical. Such models in general attempt tomeasure risk using very restricted data obtained in animals

exposed to high dose levels since adequate human data arerarely available. They are based on simplistic inferences andassumptions as to the nature and variety of carcinogenic mechanisms. Thus, choice of model and the many variables andvariances involved in the assumptions, which may be considerable, can modify the conclusions by many orders of magnitude.Further, such conclusions and assumptions cannot and havt1

not been validated by human or animal studies.Biological problems in relation to simple dose extrapolÃ¢t!. ,

are well documented, even when human data are available (16;,as illustrated by cigarette smoking. Thus, the carcinogenic effectof the latter is related to the square of the dose but the fourthpower of time (28). The relative risk at age 60 for a mansmoking 20 cigarettes a day for 20 years is about 1 order ofmagnitude less than that of a man smoking 10 cigarettes a dayfor 40 years. Similarly, the high susceptibility of hepatitis Bvirus carriers to primary carcinoma of the liver as compared tononcarriers (29) makes simplistic dose extrapolation for afla-toxin B, from rodent studies difficult.

It has been postulated that if the total molecular mechanismsof a specific carcinogenic process were understood, includingthe probability of each key or limiting step, accurate quantitative extrapolation as to the probability of impact of an exogenous factor could theoretically be made between and withinspecies (16, 26). The feasibility of this concept for very lowcarcinogenic risk exposures as distinct from pharmacokineticstudies at high doses requires consideration.

Quantitation of Probability of Rare Biological Events. Clinicalcancer is now considered the outcome of a multistage processinvolving a cascade of biochemical and biophysical eventswithin an individual cell and its microenvironment, usuallybelieved to be triggered by one or more exogenous or endogenous factors. Such events include mutation, oncogene activation, gene derepression and promotion, and changes in membrane receptors, as well as the impact of variations in hostmetabolism, immunological status, etc. (16). However, the nature as well as the relevance of individual events and theirprobability, including those which are rate limiting or critical,are often unknown.

Since most tumors are monoclonal and only one cell amongmillions apparently at equal risk gives rise to a clinical cancer,the probability of the total cascade of events leading to transformation and clinical cancer must be exceedingly low. Further,certain individual events, due to their extreme rarity and biophysical nature, can be regarded as intrinsically uncertain froma probabilistic viewpoint. Accordingly, it can be argued that thetransformation sequence in an individual cell could be regardedas essentially unique or random.

Peto et al. (30) have calculated for a human at age t years,the probability for a viable epithelial cell becoming transformedon the morrow as about 10~23f, give or take a few powers of

10, and for a mouse, a billion times greater. He points out thatfor numbers of such magnitude, variations of this degree are oflittle importance. Little (31 ) states that in the mouse fibroblastsystem, the second step in transformation is a rare event occurring with a frequency of 10* or less among initiated cells. He

concludes that quantitative expression of transformation interms of frequency per viable cell is a meaningless and artificialparameter. Klein and Klein (32) suggest that the breakage of awye-carrying chromosome is due to a randomly occurring mi-totic accident. Human cell strains and lines show 300-foldvariations in susceptibility to mouse sarcoma virus (33).

If such uncertainties exist in measuring the probabilities oftransformation in relatively simple in vitro systems, the diffi-

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culties are obvious from a biological viewpoint of giving in thewhole animal a meaningful probability to the total cascade ofevents or even to a single limiting step. The situation is evenmore complex if the interplay of the numerous hereditary andenvironmental influences modulating cellular transformationas outlined by Nicholson (34) and others (35) are taken intoconsideration. Nor can the possibility of reversibility be excluded (36, 37). Further there may possibly be qualitative differences between the effects of modulating factors at low ascompared to high doses, in contrast to what is postulated forgenotoxic agents. Moreover, the weaker the triggering or initiating stimulus, the greater is the probable impact of modulatingfactors.

Limited studies in humans predominantly based on cancersin which the strong promoting activity of cigarette smoking isinvolved have led to the assumption that multiple exposuresare synergistic. However, there are considerable in vitro and invivo data indicating that the action of mixtures are highlycomplex. Thus, while in vitro studies suggest that most genotoxic mutagenic mixes are considered to be additive (38), inhibitory as well as synergistic effects can be found and can sometimes be explained mechanistically. There are few data, in vivoor in vitro, on the effects of multiple modulating factors ormixtures, however, at very low levels of exposure.

These complexities suggest that in calculating the probabilityof cellular transformation through knowledge of individualbiological events, the situation may be analogous to forecastingthe probability of a very rare accident, such as an airplane crashor nuclear core meltdown, based on analysis of mechanisms ofprevious accidents. After an accident, many contributing eventsmay be identified. Some will usually be found to be unique,others trivial and unanticipated. The nature and sequence maydiffer from accident to accident and often no individual factorwill be found to be a critical or a key determinant. Thus, it isusually impossible to assign a meaningful numerical probabilityto the total cascade of events in view of the variables, many ofwhich are unknown, such as human error. Accordingly, knowledge of the mechanism of an accident, although complete andpresenting a logical sequence, does not necessarily permit anaccurate estimate of the probability of an identical accident inthe future unless a major critical and necessary event, such asthe failure of a major component, can be identified and itsprobability measured. In contrast, an actuarial risk, i.e., thenumber of deaths per 100 million passenger miles, can bemeasured from experience, as can the relative frequency ofgeneral classes of accident. Unfortunately, however, for lowcancer risks in humans, actuarial data are not and are unlikelyto become available due to the insensitivity of the epidemiolog-ical method. Thus, the assumption that more intensive epidemiolÃ³gica!studies will permit better quantitation of such risksmay not be true.

In conclusion, biomathematical models essentially representvalue judgments and thus, despite their increasing mathematicalsophistication, are unlikely to contribute more objective measurements of carcinogenic risks despite detailed knowledge ofmolecular events since the probability of most individual eventscannot be verified. This limitation is inherent in the rarity ofthe series of events and not on their biological or physicalnature. It is doubtful, moreover, that in the present politicalclimate, the necessary megamouse experiments to test the validity of such complex models will ever be initiated. The ED0iexperiment (i.e. based on the minimum dose necessary toproduce 1% of tumors in the experimental animals) illustratedrather than resolved the many difficulties and uncertainties in

interpreting low-level risk laboratory studies; nor, for ethicaland logistic reasons, are meaningful observational studies inhumans feasible (39). Many biologists would accordingly acceptBerenblum's (40) contention that, "In view of the great com

plexity of the carcinogenic process, it seems clear that therecannot possibly be a straightforward, direct correlation withcarcinogenesis considered as one single parameter. Nor are theavailable biological data adequate, even if this were theoreticallypossible."

These arguments apply only to low risk quantitative assessment and in no way negate the great value of pharmacokineticand molecular mechanistic studies for defining chemopreven-tion and therapeutic approaches or as a basis for makingscientific judgments on the characterization of a potential cancer risk factor. Thus, for example, pharmacokinetic data mayprovide a biological explanation for the different neoplastic aswell as toxicological responses between species (41).

Complex Carcinogenic Risk Factors: EpidemiolÃ³gica! Considerations

If the epidemiological identification of discrete carcinogensoriginating in the external environment presents difficulties,these are nonetheless recognizable as foreign to the humanorganism. Yet current evidence suggests that perhaps one-fourth to one-half of cancers in occidental males and females,respectively, are influenced by natural constituents of diet andby chemicals which are "normal" cell products or metabolites

but the mechanistic and modulating roles of which remainpoorly understood.

Where complex, subtle, and often ill-defined carcinogenicrisk factors are involved, their analysis by epidemiological techniques may often be difficult and subjected to both biologicaland statistical limitations. However, serendipitous clinical orsystematic observational studies in patients on drug therapyhave generated useful etiological hypotheses as to the biologicalnature and role of certain carcinogenic risk factors such ashormones (e.g., estrogens in endometrial cancer or prolactin inbreast cancer, etc.) (42). Nonetheless, the analysis and evaluation of complex life-style risk factors such as diet have provedunexpectedly difficult (23, 43, 44).

Associations between certain foods, macronutrients, and specific cancers have been demonstrated, e.g., high fat and breastcancer, low fiber intake and colon cancer, but these are seldomstrong and sometimes inconsistent (45, 46). In contrast to therecent decrease in heart disease in North America, due probablyin part to the major dietary changes that have occurred overthe last 40 years, no comparable changes have been observed inthe incidence of cancer of the breast, uterus, colon, and prostrate, although they are widely believed to be diet related andthe dietary trends long established. The decline in stomachcancer in many countries has been attributed to increased useof dairy products, fruit, and vegetables, and changes in foodpreservation, including increased refrigeration, antioxidant use,and decreased use of salt or a reduction in intragastric /V-nitrosocompound formation. Studies on dietary nitrates have beeninconsistent with simple V nitroso hypotheses and suggestmore complex interactions (47). If such uncertainties apply tomajor dietary components or cancers, which have been extensively studied, the difficulty of isolating the carcinogenic oranticarcinogenic impact of the many biologically active chemical microconstituents in the diet, natural or man-made, byepidemiological studies in humans is obvious (8).

Large-scale population prospective cohort studies based on

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detailed dietary analysis are logistically expensive and oftenprove to be uninformative. The Framingham heart study isunlikely ever to be repeated and unfortunately many potentialparameters of interest to oncologists were not included in theoriginal protocol. The interplay between dietary, hormonal, andsocioeconomic factors in humans (2, 4) complicates evaluationof individual risk factors. Thus, high-fat diets, late pregnancyand high living standards, all risk factors in breast carcinoma,usually occur in the same segments of the population.

Ecological correlation studies between countries and communities are frequently attempted. Although usually consideredhypotheses-generating or "fishing" expeditions, such studies

have unfortunately tended to become increasingly used fordrawing definitive causal associations, despite their well-recognized limitations and frequent inconsistencies, since the individual may not be identified with his diet of many years earlier(23).

After an extensive review, the National Academy of Sciences(43) could only conclude that while accepting that most majorcancers are influenced by diet, "the data are not sufficient to

quantitate the contribution of diet to the overall cancer risk orto determine the percent reduction in risk that might beachieved by dietary modifications." Accordingly, recommend

ing unequivocal guidelines requiring major and possibly unnecessary' changes in a pleasurable cultural habit are difficult.

Unfortunately, experimental dietary studies usually implygross dietary changes or the administration of specific nutrientsat almost pharmacological levels, which may not reflect themore subtle changes likely to be involved in human carcinogen-esis. It seems unlikely that traditional observational studies willfurther resolve these difficulties or facilitate discriminationbetween populations unless specific dietary or other life-stylecharacteristics can be better defined. Accordingly, it is logicalthat major research efforts be directed to defining such riskfactors more objectively, using approaches based on biochemical and molecular epidemilogy.

Individual Susceptibility and Prevention

Investigations on migrants, while emphasizing the predominance of environmental factors, do not exclude important interactions between genetic and environmental factors (48, 49)and a number of syndromes have been identified associatedwith increased cancer risks (50). Major conceptual contributions in molecular cytogenetics have been made by Knudson(48). He points out that inherited susceptibility depends ongenetic changes in somatic cells, such as activated proonco-genes, deficient repair of genetic damage, fragile sites, or oncogene mutation or recessive antioncogene mutation, etc. (48,50). His studies on retinoblastoma are somewhat unique in thatthe theoretical calculations are in accord with the observedfrequency of first mutation and later tumor development inaffected individuals.

If susceptibility depends on one or two key gene loci, analysisand identification through modern cytogenetic or biochemicaltechniques may be possible, such as susceptibility to breastcancer in ataxia-telangiectasia hÃ©tÃ©rozygotes(51) or bladdercancer in individuals deficient in yV-acetyltransferase. However,if multiple genes are involved, susceptibility will be polygenicand may appear random and difficult to analyze meaningfullyin a large population, especially where several environmentalfactors of uncertain impact may be involved. Thus, for example,an individual with even a 50-fold increase in susceptibility dueto recessive gene would be very difficult to detect in an epide

miolÃ³gica! study (49). Such studies are subject to the samebiostatistical limitations as occur with multiple interacting risksof low probability. Accordingly, it should not be assumed thatsequencing the human gene or the identification of sensitiveindividuals (52) will necessarily provide feasible preventativeapproaches through environmental control for many cancers.However, identification of individuals susceptible to tobaccosmoke or evidence of ability to metabolize or detoxify chemicalsoccurring in the work environment would of course have majorimplications for specific cancers.

Future Developments in Epidemiology and Prevention

For the reasons given above, there would appear to be definitive limitations to cancer prevention based only on traditionaleliminatory approaches, whether related to low level chemicalexposures or isolated dietary changes. However, epidemiolÃ³gica! investigations will continue to provide important contributions to cancer control.

Traditional Studies

The differences in cancer experience which are found betweenvarious countries (1) and communities (53, 54) indicate thattheoretically, major possibilities for prevention still exist. Thus,the black male in San Francisco has double the risk of developing cancer as compared to his countryman of Japanese ethnicorigin (54). Furthermore, significant differences between certain religious groups, specific occupations, and the generalUnited States population are well known. Available data suggest that many of these differences are partly related to knowncauses, including tobacco (4) and socioeconomic conditions (21)for which classical eliminatory approaches are feasible (55).Priority, of course, should continue to be given to the controlof such cancers.

While improved public health measures in most modernstates make it unlikely that many new strong carcinogens willenter the environment in the future, such a possibility cannotbe excluded. Furthermore, well-recognized "old" chemical hazards may surface unexpectedly in new "high-tech" industries

and in inadequately supervised small plants, notably in thirdworld countries. It is probable that epidemiological studies willcontinue to identify unusual variations in cancer incidence andto investigate potential causal associations as illustrated bydomestic radon gas. These observations justify routine monitoring surveillance studies, especially where excessive exposuresare suspected. Such activities essentially represent the cancerequivalent of the routine public health surveillance carried outfor communicable diseases.

For the reasons above, notably lack of sensitivity, many suchstudies will be "negative," especially where exposures are sev

eral orders of magnitude lower than in an occupational setting,as around waste disposal sites (56), irrespective of whethercancer or some biomarker is used as an end point. Thus, theymust be interpreted with care and not be undertaken withoutreason since, unfortunately, spurious causal associations orrandom cancer clusters may lead to unnecessary public concernwhich will not always be allayed, even by well-conducted epidemiological studies.

Developments in Biochemical and Molecular Epidemiology

The value of integrating laboratory investigations into epidemiological studies has long been recognized (1,2, 57, 58) and

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motivated the direction of the early program of the International Agency for Research on Cancer. Studies in the 1950sand 1960s were predominantly related to identifying virusmarkers, hormonal patterns, or tissue analysis for suspectedcarcinogens, e.g., dichlorodiphenyldichloroethylene. Today, elegant and sensitive laboratory techniques such monoclonalantibodies, DNA hybridization probes, rapid screening testtechniques, etc., permit the direct or indirect identification,measurement, and evaluation of multiple cellular processes inin vivo and in vitro systems (14, 15, 59, 60) in addition tomodern analytical chemical methods (61). Harris (60) has examined the possible use of in vitro models utilizing humantissues and cultures to permit increased understanding of theprocesses controlling growth, differentiation, and neoplastictransformation in human cells, including carcinogen metabolism, DNA damage and repair, and the role of oncogenes.Nonetheless, major difficulties still remain in attempting extrapolation of carcinogenic data and knowledge of mechanismsfrom laboratory animals to humans and from heterogeneouspopulations to individuals. The complexities of relating transformation to a single defined agent are well illustrated byDuesberg (62) for the retroviruses.

In vitro neoplastic transformation in human cells is difficultand may possibly be intrinsically different from transformationin rodent cells (60). However, the study of growth differentiation in normal and neoplastic human epithelial cells and thehypothesis of selective clonal expansion and the potentialsuppression of carcinogenesis by many techniques in culture dosuggest theoretical possibilities to intervene in key mechanismscritical to transformation and tumor induction.

At present, great interest in molecular epidemiology is focused on biomarkers. These are of many types. Some might bebest described as specific predictors of neoplasia or preneoplasia, others as indicators of increased susceptibility to cancer orof exposures to exogenous carcinogenic agents. Considerablehope is being placed on their employment in epidemiology sincethey theoretically can provide guidelines, not only to molecularmechanisms but also to potential carcinogenic triggers (14, 15).Thus, carcinogens such as aflatoxin B, can be activated to formcarcinogenic DNA adducts in cultures of human tissues. Otherbiomarkers include oncogenes, antioncogenes, membranechanges, growth factors, hormonal receptors, enzymes, micronuclei, etc. (14, 15, 59, 63-69). Carcinogenic metabolites mayalso prove informative such as intragastric or intraoral formation of TV-nitroso compounds (47, 70). Chromosomal abnormalities are frequent in human cancers and may be specificallyassociated with certain tumor types, but their specific biologicalrelevance and significance are usually not known (71). Similarlimitations relate to the detection and evaluation of transforming genes in tumors.

From the viewpoint of identifying exogenous factors, thereare significant variations relative to carcinogen metabolism,DNA damage, and repair in somatic activities that may occurin various tissues of individuals and outbred animals which areof significance in inferring biological extrapolation to low doses(60). The value of a specific biomarker requires that it bedemonstrated to predict a specific end point, e.g., tumor ordefined preneoplastic lesion, or provide a measure or index ofprevious exposure to a specific chemical (14, 69) or virus (72).This is true whether it reflects a key molecular event or is asurrogate measure. The extreme sensitivity of the methods usedin the identification of molecular markers, however, subjectstheir evaluation to the same biostatistical limitations inherentin studying any low level discriminator. It may prove difficult

to evaluate a single biomarker, i.e., a DNA adduci, as predictingcancer or exposure to a very low level chemical risk in thepresence of many confounding adducts due to other ambientcarcinogens of equal plausibility. While DNA adducts are receiving great attention, DNA damage obviously reflects onlyone aspect in a complex process. Thus, while it is possible tomeasure carcinogenic DNA adducts in cells of individuals exposed to carcinogenic chemicals and chemotherapeutic agents,it is unlikely that they will necessarily be quantitative predictorsof cancer risk, even though they measure "DNA lesions considered to be important in carcinogenesis" (60). Inconsistencies

between adduct formation, transformation, and cancer induction have also been reported (67-69).

Biomarkers, however, can offer useful information in a number of situations, including: (a) possible identification of asuspected high-risk group in an occupational setting, whetherthe marker relates to a specific chemical (14, 64, 66), biologicalagent, or metabolite; (b) provide objective support for a "negative" epidemiological study where the "exposed" population

shows no quantitative differences from an unexposed population in terms of the suspected factor(s); (c) identification ofmetabolic variations indicative of individual susceptibility to axenobiotic chemical (14, 70); and (d) the comparative evaluation of potential carcinogenic mechanisms in humans.

There are, however, ethical problems in informing an individual as to his possession of a marker of uncertain significancewhen no practical benefit can be offered. Further, where invasivetechniques are required, their use may not necessarily be without risk. For the above reasons, the view that biomarkersprovide a definitive breakthrough to the investigation of suspected low level potential carcinogenic risks, for example, associated with toxic waste deposits or water or air pollution, andthus offer new eliminatory approaches may be premature.

Interventive Strategies

It is obvious that major changes in diet, cultural, or sexualhabits may prove difficult to implement and may be sociallyunacceptable in large populations unless the latter are convincedof unequivocal benefit at the individual level. As argued above,current epidemiological and laboratory fundamental researchincreasingly indicates that many human cancers of unknownetiology arise from multiple interactions involving both hostand environment, the individual and critical components ofwhich may prove difficult to identify. However, progress infundamental research increasingly offers possibilities for eventual control of cellular mechanisms or modulating factors involved in transformation and cancer induction through interference ("a spanner in the works") (10, 14, 73-76) rather than

by the elimination of a single life-style factor or an ambientchemical pollutant. Intervention implies both chemopreventa-tive and chemotherapeutic approaches.

Concepts and developments in chemoprevention were recently reviewed in this journal (37, 76). Studies of endocrine-dependent tumors have suggested a number of possibilitiesthrough hormonal control, and the impact of oral contraceptives on ovarian and endometrial cancers is well known (75).Further, the development of some form of drug therapy mimicking the critical determinants of first pregnancy or late men-arche that could retard or prevent many breast cancers appearstheoretically feasible, provided that such a therapy would beadequately tested and be socially acceptable in healthy populations. Viruses may be necessary determinants for certain cancers, e.g., hepatitis B virus in primary liver carcinoma in Africa

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or human papilloma virus in cervical cancer (72). Vaccines offeran obvious approach to active intervention for such cancers andare being tested.

While there are many hypotheses for cancer control throughchanges in the dietary environment, such as the administrationof retinoids and antioxidants or modification of fat and fiberintake, their effectiveness remains to be established.

It is anticipated that epidemiology will contribute to suchefforts through well-executed, integrated laboratory and fieldstudies and rigorously controlled clinical intervention trials ofchemopreventative technologies, vaccines, etc. Such trials require considerable logistic and technical effort and should notbe undertaken lightly. Thus, the attempt of the InternationalAgency for Research on Cancer to reverse esophageal cancerby dietary supplements in China showed no effect after 1 year.Despite the major further effort involved, further follow-up isclearly required before the negative results can be accepted.

EpidemiolÃ³gica! studies must not only be directed to theidentification of carcinogenic factors but also give greater attention to inverse relationships and the characteristics of populations at a low risk to cancer, including socioeconomic factors,with a view to seeking clues to inhibitory mechanisms. On theother hand, if chemoprevention through modest dietary ortherapeutic manipulation is shown to be impractical, thenchemotherapy represents the most logical alternative. Bothapproaches are dependent on essentially similar lines in basiccarcinogenesis research.

General Comments

There is a large group of cancers in humans for which majorcauses and consequent preventative strategies are well defined.However, there still remains much neoplastic disease with asignificant environmental component for which no unequivocalguidelines for prevention can be given due to the inherentbiological and biostatistical limitations to identifying controllable etiological factors. Two divergent strategies have developed for the control of such cancers. First, there are largeregulatory programs based on fairly rigid quantitative riskassessment designed to control or eliminate the evergrowingnumber of potential carcinogens, mutagens, and promotersusually present in minute quantities in the ambient environment. In contrast, the biological approach attempts to analyzethe molecular and mechanistic biological base of transformationand modulation with the objective of eventually interveningactively in the carcinogenesis process.

The past effectiveness of control measures on occupationalcancer and the ecological benefits of much regulatory activityare unquestionable. However, it is important to distinguishbetween environmental controls for ecological reasons andthose enacted to reduce cancer risks. Exact figures are difficultto obtain, but calculations of the direct or indirect costs ofenvironmental controls indicate enormous financial expenditures and estimates ranging up to several per cent of the grossnational product have been reported (77). Such controls areoften enacted on the premise that they will significantly reducethe human cancer burden. Irrespective of the exact cost, it isnot unreasonable to regard this expenditure as a large if not thelargest national effort ostensibly directed to cancer control. Itseffectiveness and relevance to health as distinct from the ecological component should be accordingly critically examined.

Despite intense epidemiolÃ³gica! efforts, the list of carcinogenic chemicals and occupations established in humans has notexpanded significantly in the last 15 years although the number

of carcinogens, mutagens, and enhancers (both man-made andnatural) identified in animal bioassays continues to grow. Moreover, there is little objective evidence as distinct from theoreticalcalculations that regulation of minute quantities of ambientpollutants has had a significant impact on the overall burdenof cancer in recent years apart from classical high-risk occupational and point source situations (2-4). Exposures to mostchemicals of concern began during and after World War II andsufficient time should have elapsed by now to show someimpact. Nevertheless, the emotive nature of cancer as a diseasehas led to the argument that one cannot wait for "dead bodies"

before enforcing regulatory controls irrespective of their effectiveness. This argument is meaningless for de minimis risks,since it is impossible to prove the negative. On the other hand,it has great weight among the public and among many well-intentioned people with limited scientific experience in chemical carcinogenesis as illustrated by the California Safe DrinkingWater and Toxic Enforcement Act of 1986, adopted by Proposition 65.

The use of quantitative risk assessment as a surrogate measure of the danger of potential ambient carcinogens has beendiscussed. Despite lack of confirmation and known limitations,definitive claims are made by some as to the exact number ofcancers that are or will be caused by an exposure or will beprevented as a result of certain regulatory actions (78). Suchclaims confuse prudent control of unnecessary exposures topotential risks with actual cancer prevention.

While molecular mechanistic studies may not necessarilycontribute to the establishment of generic guidelines to measurecancer risks of low probability, they are of inestimable value inrisk characterization. Thus, competent scientists, using data ontype of carcinogen exposures, pharmacokinetics, comparativemetabolites, etc., can often provide sound opinions as to theprobable significance to humans of potential carcinogenic hazards which can be used for prioritization and to distinguish thetrivial from the significant, even when the data are incomplete.Such judgments may be more meaningful and scientifically lesssubjective than theoretical estimates based on biomathematicalmodels. The latter, however, can provide legitimate input tothe analysis of complex interactions and their operation, butmathematical elegance cannot substitute for reality and scientific judgment. The question is still essentially under whatconditions a suspected factor, e.g., vinyl chloride or unsaturatedfat, constitutes a hazard to humans. Thus, at some point wemust rely on scientific judgment as to the triviality or significance of a risk, and such judgment must remain the essentialingredient of any rational public health policy.

As discussed above, developments in cellular biology (including molecular epidemiology) indicate the possibility throughidentification of key mechanisms of directly or indirectly inhibiting or interfering in carcinogenesis (through either chemoprevention or cure). Such research represents the logical outcomeof Berenblum's concepts (10) and has been emphasized by theAACR1 Public Affairs Committee report (76) and the present

National Cancer Institute program (79).Unfortunately, such concepts which are widely accepted by

many oncologists are almost completely ignored by regulatoryor legislative bodies in their perception of cancer control strategies. More formal input to the public arena by scientists withrecognized expertise in chemical carcinogenesis would appearto be essential to ensure that such complex and important

1The abbreviation used is: AACR, American Association for Cancer Research.

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scientific issues involved are adequately discussed.

Role of the AACR

As a general rule, the national professional societies within acountry contain the majority of recognized scientists in a specific discipline. The AACR remains the traditional professionaland academic society for chemical carcinogenesis, althoughtoday many epidemiologists, virologists, cellular biologists, etc.,involved in carcinogenesis may belong to other societies. Indetermining to what extent policies directed to controllingchemical cancer risks in the United States are influenced by theAACR, I have reviewed formal input by members to somebodies.

In 1983, a committee of the National Research Council wascharged to report on the management of risk assessment in thefederal government with emphasis on the role of chemicals incancer (25). There was one member of the AACR among thecommittee members and one among the 35 external advisers.No other recognized leader in molecular biology or carcinogenesis appears to have been formally involved. The recent National Academy of Science report on the impact of pesticidecontamination which emphasized that a high risk existed hadonly one member of AACR among its 16 associates (78). Theseimportant conclusions were based on biomathematical models,the basis of which was not critically examined. The Environmental Protection Agency is the lead body in regulating carcinogenic hazards in the ambient environment in the United States.Only 1 of the 58 members of the Scientific Advisory Board inJune 1986 and only 2 of the 7 members of the subcommitteeon Carcinogenicity Guidelines were listed as members of theAACR. Of 19 members of the influential interagency committeereviewing the nature of chemical carcinogenesis in 1985 (16),only 3 were AACR members. The few AACR members mentioned clearly do yeoman service, inasmuch as the same namesrecur. Obviously there is considerably more input by AACRmembers to regulatory activities as advisors, etc. However, thiscontribution is difficult to evaluate because they cannot beidentified as responsible for the final report.

Whether these bizarre observations reflect a failure by theagencies to recruit formally from the society or an unwillingnessby academic scientists to be involved in an area which they mayregard as political, nonscientific, or trivial is a matter forspeculation. Certainly the subject of risk assessment, althoughemphasized by regulators as a major "new science" on which

to base cancer policy, is generally ignored by oncologists. TheEnvironmental Protection Agency stated that only 4 of the 62comments received for its guidelines for carcinogenic risk assessment were from academic institutions (26).

These comments are not meant to disparage scientists fromother disciplines, who are well represented and whose competence in carcinogenesis may be equal to or greater than that ofmembers of the AACR. Nor is it clear that regulatory policieswould be changed since considerable scientific judgment hasbeen exercised despite use of models, as least in some cases(80). Nonetheless, the question remains as to why there is solittle formal input by members of the AACR in a scientific areaof such major public concern.

Conclusions

The need to apply and intensify the control of known causesof cancer, especially tobacco and chemicals in the workplace, is

obvious. However, current research indicates that there arelimitations to cancer control through regulation or simplisticcontrol of life-style factors. In contrast, such research offers thepossibility of developing feasible techniques to interfere activelyin carcinogenic mechanisms. Such techniques will be based onfundamental and basic research and appear to me to representthe most logical scientific method to reducing the burden ofhuman cancer in the future. Where chemopreventative strategies are lacking, therapy seems to be the logical alternative, andboth depend on fundamental molecular research. This viewoffers no immediate short-term success but rather a long-termcommitment in manpower and funding. Despite clearly definedgoals and targets, there is no certainty as to the time frame oreffectiveness of individual projects. This fact, based on currentknowledge, although disappointing, must be accepted but isdifficult to convey to the public, legislative bodies, and publicinterest groups who are inexperienced in the complexities andneeds of modern biology. Consequently, immediate control ofputative environmental carcinogens at minute levels or recommendations for major changes in "life-style," including dietary

patterns, have considerably greater public appeal irrespective ofeffectiveness or necessity. Over the last two decades, moreover,such approaches have developed large constituencies in industry, academia, toxicological laboratories, and government aswell as among environmental activists. Thus, major publicresources and efforts are directed predominantly to detectingbut not to evaluating environmental hazards. According to theConservation Foundation (81), "tens of billions of dollars are

being invested to comply with environmental standards butlittle, comparatively, is being invested to improve the scientificbasis for the standards."

Such efforts are operating outside the usual norms of scientific scrutiny to determine effectiveness, intellectual content,and financial justification. Accordingly, it may not be surprisingto find that a recent government-sponsored task force established to recommend on research in environmental health policyseriously suggested that the usual statistical restraints in evaluating environmental agents should be relaxed in the name ofprevention (Ref. 27, p. 288).

While differences in opinion as to the direction of researchare part of the normal development of science, fear of canceramong the public may have undue impact on the direction ofcancer control at the legislative level. However, if the argumentspresented above are valid, much of this national effort expendedin the name of cancer control is directed to strategies which areboth costly and apparently ineffective. The danger of emphasison the benefits of certain control measures based on quantitativerisk assessment lies not in their intent and irrelevance but intheir false accuracy. This may maximize trivial risks, causeunnecessary public concern, and thus divert limited resourcesaway from more effective cancer control strategies and othermore important national social and health goals.

Holland (82) has emphasized that "cancer research is less

dependent on individual breakthrough than on steady progressover a number of years." The fact that this progress has been

apparently slower and less spectacular than originally hopeddoes not mean that the war against cancer is being lost, asfrequently announced, but rather that the biological problemsare more complex than anticipated in 1970 (83). Moreover,such lack of progress in no way negates the statement ofElizabeth Miller (84) that cancer control strategies must bebased on scientific knowledge and methods. These requireintellectual integrity and scholarship. It is postulated that thedirection of current cancer research control activities should be

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of concern to members of the AACR and that the challengeposed by Shear in his presidential address (85) as to whetherthe AACR will accept a stronger role in the public arena canno longer be ignored. Failure to do so may distort the issues byencouraging attacks on the opinions of respected scientistssponsored by those unfamiliar with scientific developments(86).

References

1. Higginson, J. Present trends in cancer epidemiology. Proc. Can. CancerConf.,Â«:40-75, 1968.

2. Wynder. E. 1 .. and Gori, G. B. Contribution of the environment to cancerincidence: an epidemiologie exercise. J. Nati. Cancer Inst., 58: 825-832,1977.

3. Higginson, J., and Muir, C. S. Environmental carcinogenesis: misconceptionsand limitations to cancer control. J. Nati. Cancer Inst., 63:1291-1298, 1979.

4. Doll, R., and Peto, R. The causes of cancer: quantitative estimates ofavoidable risks of cancer in the United States today. London: Oxford University Press, 1981.

5. Berenblum, I. Theoretical and practical aspects of the two-stage mechanismof carcinogenesis. In: A. C. Griffin and C. R. Shaw (eds.). Carcinogens:Identification and Mechanisms of Action, pp. 25-36. New York: RavenPress, 1979.

6. Weinstein, I. B., Caggori-Celli, s , Kurschneuer, P., et u/.Multistage carcinogenesis involves multiple genes and multiple mechanisms. ///: Cancer Cells.The Transformed Phenotype, pp. 229-237. Cold Spring Harbor, NY: ColdSpring Harbor Laboratory, 1984.

7. Epstein, S. S. The Politics of Cancer. San Francisco: Sierra Club Books,1978.

8. Ames, B. N., Magaw, R., and Gold, L. S. Ranking possible carcinogenichazards. Science (Wash. DC), 236: 271-280, 1987.

9. Berenblum, I. Chemical carcinogenesis: predictive value of carcinogenicitystudies. Br. J. Cancer, 41:490-493, 1980.

10. Berenblum, I. Cancer prevention as a realizable goal. In: 3. G. Fortner andJ. E. Rhoads (eds.). Accomplishments in Cancer Research 1980, pp. 101-104. Philadelphia: J. B. Lippincott Co., 1980.

11. RoÃhman, K. J. Causation and Causal Inference. In: D. Schottenfeld and J.F. Fraumeni, Jr. (eds.), Cancer Epidemiology and Prevention, pp. 15-29.Philadelphia: W. B. Saunders, 1982.

12. International Agency for Research on Cancer. IARC Monographs on theEvaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 40, pp.1-32. Lyon, France: International Agency for Research on Cancer, 1986.

13. MacMahon, B. EpidemiolÃ³gica! methods in cancer research. Yale J. Biol.Med., 37: 508-522, 1965.

14. Harris, C. C. (ed.). Biochemical and Molecular Epidemiology of Cancer.New York: Alan R. Liss, 1986.

15. Berlin, A., Draper, M.. Hemminki. K.. and Vainio, H. (eds.). MonitoringHuman Exposure to Carcinogenic and Mutagenic Agents. IARC ScientificPublications No. 59. Lyon, France: International Agency for Research onCancer, 1984.

16. United States Interagency Staff Group on Carcinogens. Chemical carcinogens: a review of the science and its associated principles. Environ. HealthPerspect., 67: 201-282, 1986.

17. Day, N. E. Statistical considerations. In: N. J. Wald and R. Doll (eds.),Interpretation of Negative EpidemiolÃ³gica) Evidence for Carcinogenicity.IARC Scientific Publications No. 65, pp. 13-27. Lyon, France: InternationalAgency for Research on Cancer, 1985.

18. Wynder, E. L. Workshop on guidelines to the epidemiology of weak associations. Prev. Med., 16: 139-141, 1987.

19. Roman, E., Beral, V., Carpenter, L., Watson, A., Barton, C., Ryder, H., andAston, D. L. Childhood leukaemia in the West Berkshire and Basingstokeand N'orili Hampshire District Health Authorities in relation to nuclear

establishments in the vicinity. Br. Med. J., 294: 597-602, 1987.20. Cook-Mozaffari, P. Cancer near nuclear installations. Lancet, /: 855-856,

1987.21. Office of Population Censuses and Surveys. Occupational Mortality. The

Registrar General's Decennial Supplement for England-Wales, 1970-72.Series DS No. I. London: Her Majesty's Stationery Office, 1978.

22. Logan, W. P. D. Cancer Mortality by Occupation and Social Class 1851-1971. IARC Scientific Publications No. 36. Lyon, France: InternationalAgency for Research on Cancer, 1982.

23. Zaridze, D. G., Muir, C. S., and McMichael, A. J. Diet and cancer: value ofdifferent types of epidemiological studies. In: J. V. Joossens, M. J. Hill, andJ. Geboers (eds.). Diet and Human Carcinogenesis, pp. 221-233. New York:Excerpta Medica, 1985.

24. Hemminki, K., and Vainio, H. Human exposure to potentially carcinogeniccompounds. In: A. Berlin, M. Draper, K. Hemminki, and H. Vainio (eds.),Monitoring Human Exposure to Carcinogenic and Mutagenic Agents. IARCScientific Publications No. 59, pp. 37-45. Lyon, France: InternationalAgency for Research on Cancer, 1984.

25. Committee on the Institutional Means for Assessment of Commission onLife Sciences, National Research Council. Risk Assessment in the Federal

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

Government: Managing the Process. Washington, DC: National AcademyPress, 1983.Environmental Protection Agency. Guidelines for carcinogenic risk assessment. Part II. Fed. Regist., 51 (185): 33992-34003, 1986.Third Task Force for Research Planning in Environmental Health Sciences.Human Health and the Environment. Some Research Needs. Bethesda, MD:National Institutes of Health. 1984.Peto, R. Epidemiology, multistage models, and short-term mutagenicity tests.In: H. H. Hiatt, J. P. Watson, and J. A. Winsten (eds.). Origins of HumanCancer, pp. 1403-1428. Cold Spring Harbor, NY: Cold Spring HarborLaboratory, 1977.Beasley, R. P., Wang, L. Y., Lin, C. C., and Chien, C. S. Hepatocellularcarcinoma and hepatitis B virus. Lancet, 2:1129-1133, 1981.Peto, R., Parish, S. E., and Gray, R. G. There is no such thing as aging, andcancer is not related to it. In: A. Likachev, V. Annisimov. and R. Montesano(eds.). Age-related Factors in Carcinogenesis. IARC Scientific PublicationsNo. 58, pp. 43-53. Lyon, France: International Association for Research onCancer, 1985.Little, J. B. Cellular mechanisms of oncogenic transformation in vitro. In: T.Kakunaga and H. Yamasaki (eds.), Transformation Assay of Established CellLines: Mechanisms and Application. IARC Scientific Publications No. 67,pp. 9-29. London: Oxford University Press, 1985.Klein, G., and Klein, E. Conditioned tumorigenicity of activated oncogenes.Cancer Res., 46: 3211-3224, 1986.Klement, V., Freedman, M. H., McAllister, R. M., Nelson-Rees, W. A., andHeubner, R. Differences in susceptibility of human cells to mouse sarcomavirus. J. Nati. Cancer Inst., 47:65-71, 1971.Nicholson, G. L. Tumor cell instability, diversification, and progression tothe metastatic phenotype: from oncogene to oncofetal expression. CancerRes., 47: 1473-1487, 1987.BÃ¶rzsÃ¶ny,M., Lapis, K., Day, N. E., and Yamasaki, H. (eds.). Models,Mechanisms and Etiology of Tumour Promotion. IARC Scientific Publications No. 56. London: Oxford University Press, 1984.Sachs, L. Cell differentiation and bypassing of genetic defects in the suppression of malignancy. Cancer Res., 47: 1981-1986, 1987.National Institutes of Health Workshop Report. Cellular and molecularmechanisms for suppression and reversion of tumorigenicity: a chemicalpathology study section workshop. Cancer Res., 47: 2514-2520, 1987.Waters, M. D., Nesnow, S., Huisingh, J. L., Sandhu, S. S., and Claxton, L.(eds.). Application of Short-Term Bioassays in the Fractionation and Analysis of Complex Environmental Mixtures. New York: Plenum PublishingCorp., 1978.National Center for Toxicological Research, Society of Toxicology. A reporton the workshop on biological and statistical implications of the ID,,, studyand related data bases. Fund. Appi. Toxicol., 3: 129-160, 1983.Berenblum, I. The problem of quantitative carcinogenesis. In: The JerusalemSymposia on Quantum Chemistry and Biochemistry, Physico-ChemicalMechanisms of Carcinogenesis, pp. 321-324. Jerusalem: Israel Academy ofSciences and Humanities, 1969.Ramsey, J. C., and Gehring, P. J. Application of pharmacokinetic principlesin practice. Fed. Proc., 39: 60-65, 1980.Armstrong, B. Endocrine factors in human carcinogenesis. In: H. Bartsch,B. Armstrong, and W. David (eds.). Host Factors in Human Carcinogenesis.IARC Scientific Publications No. 39. Lyon, France: International Agencyfor Research on Cancer, 1982.Committee on Diet, Nutrition and Cancer, National Research Council. Diet,Nutrition and Cancer. Washington, DC: National Academy Press, 1982.Higginson, J. Summary: nutrition and cancer. Cancer Res., 4.)(Suppl.):2515s-2518s, 1983.Jensen, O. M., MacLennan, R., and Wahrendorf, J. Diet, bowel function,fecal characteristics, and large bowel cancer in Denmark and Finland. Nutr.Cancer, 4:5-19, 1982.WilleÂ«,W. C., Stampfer, M. J., Colditz, G. A., Rosner, B. A., Hennekens,C. H., and Speizer, F. E. Dietary fat and the risk of breast cancer. N. Engl.J. Med., 316: 22-28, 1987.Forman, D. Gastric cancer, diet, and nitrate exposure. Br. Med. J., 294:528-529, 1987.Knudson, A. G., Jr. Genetics of human cancer. Annu. Rev. Genet., 20: 231-251, 1986.Doll, R. Cancer: a world-wide perspective. In: C. C. Harris (ed.). Biochemicaland Molecular Epidemiology of Cancer, pp. 127-134. New York: Alan R.Liss, 1986.Knudson, A. G., Jr. Hereditary cancer, oncogenes, and antioncogenes. CancerRes.,45: 1437-1443,1985.

Swift, M., Reitnauer, P. J., Morrell, D., and Chase, C. L. Breast and othercancers in families with ataxia-telangiectasia. N. Engl. J. Med., 316: 1289-1294, 1987.Dulbecco, R. A turning point in cancer research: sequencing the humangenome. Science (Wash. DC), 231: 1055-1056, 1986.Pickle, L. W., Mason, T. J., Howard, N., Hoover, R., and Fraumeni, J. F.,Jr. Atlas of U. S. Cancer Mortality Among Whites: 1950-1980. Washington,DC: United States Department of Health and Human Services, 1987.Young, J. L., Percy, C. L., and AsirÃ©,A. J. Surveillance, Epidemiology, andEnd Results: Incidence and Mortality Data, 1973-77. National CancerInstitute Monograph 57. Bethesda, MD: United States Department of Healthand Human Services, 1981.Bailar, J. C., Ill, and Smith, E. M. Progress against cancer? N. Engl. J.Med., 314: 1226-1232, 1986.

1388




56. Grisham, J. W. Health Aspects of the Disposal of Waste Chemicals. Elms-ford, NY: Pergamon Press, 1986.

57. Higginson, J. Metabolic aspects of host environment relationships: an overview. In: R. Doll, and I. Vodopija (eds.). Host Environment Interactions inthe Etiology of Cancer in Man. IARC Scientific Publications No. 7. Lyon,France: International Agency for Research on Cancer, 1973.

58. Weisburger, J. H., Cohen, L. A., and Wynder, E. L. On the etiology andmetabolic epidemiology of the main human cancers, pp. 567-602. In: H. H.Hiatt, J. D Watson, and J. A. Winsten (eds.). Cold Spring Harbor Conferences on Origins of Human Cancer, Vol. 4. Cold Spring Harbor, NY: ColdSpring Harbor Laboratory, 1977.

59. Singer, B., and Bariseli. H. (eds). The Role of Cyclic Nucleic Acid Adductsin Carcinogenesis and Mutagenesis. IARC Scientific Publications No. 70.Lyon, France: International Agency for Research on Cancer, 1986.

60. Harris, C. C. Human tissues and cells in carcinogenesis research. CancerRes., 47: 1-10, 1987.

61. Geyer, H., Scheunen, I., and Korte, F. Bioconcentration potential of organicenvironmental chemicals in humans. Regu. Toxicol. Pharmacol., 6: 313-347, 1986.

62. Duesberg, P. H. Retroviruses are carcinogens and pathogens: expectationsand reality. Cancer Res., 47:1199-1220, 1987.

63. Perera, F. P., and Weinstein, I. B. Molecular epidemiology and carcinogen-DN A adduci detection: new approaches to studies of human cancer causation.J. Chronic Dis., 35: 581-600, 1982.

64. Bausch, H. The role of cyclic nucleic acid base adducts in carcinogenesis andmutagenesis. In: B. Singer and H. Bartsch (eds.). The Role of Cyclic NucleicAcid Base Adducts in Carcinogenesis and Mutagenesis. IARC ScientificPublications No. 70, pp. 3-14. Lyon, France: International Agency forResearch on Cancer, 1986.

65. Bryant, M. S., Skipper, P. L., Tannenbaum, S. R., and Madure, M. Hemoglobin adducts of 4-aminobiphenyl in smokers and nonsmokers. Cancer Res.,Â¥7:602-608, 1987.

66. Haugen, A., BÃªcher, G., Benestad, C., Vahakangas, K., Trivers, G. E.,Newman, M. J., and Harris, C. C. Determination of polycyclic aromatichydrocarbons in the urine, benzo(a)pyrene diol epoxide-DNA adducts inlymphocyte DNA, and antibodies to the adducts in sera from coke overworkers exposed to measured amounts of polycyclic aromatic hydrocarbonsin the work atmosphere. Cancer Res., 46: 4178-4183, 1986.

67. DiGiovanni, J., Sawyer, T. W., and Fisher, E. P. Correlation betweenformation of a specific hydrocarbon-deoxyribonucleoside adduci and tumor-initiating activity of 7,12-dimethylbenz(a)anthracene and its 9- and 10-monofluoro derivatives in mice. Cancer Res., 46:4336-4341, 1986.

68. Barnstetter, D. G., Stoner, G. D., Schut, H. A., Senitzer, D., Conran, P. B.,and Goldblatt, P. J. Ethylnitrosourea-induced transplacental carcinogenesisin the mouse: tumor response, DNA binding, and adduci formation. CancerRes., 47: 348-352, 1987.

69. Wild, C. P., Umbenhauer, D., Chapot, B., and Montesano, R. Monitoringof individual human exposure to aflatoxins (AF) and A'-nitrosamines (NNO)by immunoassays. J. Cell. Biochem., JO: 171-179, 1986.

70. Jensen, D. E., Stelman, G. J., and Spiegel, A. Species differences in blood-mediated nitrosi idiiu'i illUK-denitrosation. Cancer Res., 47: 353-359, 1987.

71. Nowell, P. C., and Croce, C. M. Chromosomes, genes and cancer. Am. J.Pathol., /25.-8-15, 1986.

72. Gupta, J., Pilotta, S.. Rilke, F., and Shah, K. Association of human papillo-mavirus type 16 with neoplastic lesions of the vulva and other genital sitesby in situ hybridization. Am. J. Pathol., 127: 206-215, 1987.

73. Sporn, M. B., Roberts, A. B., Wakefield, L. M., and Assoian, R. K. Transforming growth factor-/^: biological function and chemical structure. Science(Wash. DC), 233: 532-534, 1986.

74. Buset, M., Lipkin, M., Winawer, S., Swaroop, S., and Friedman, E. Inhibitionof human colonie epithelial cell proliferation in vivo and in vitro by calcium.Cancer Res., 46: 5426-5430, 1986.

75. Centers for Disease Control, National Institute of Child Health and HumanDevelopment. Combination oral contraceptive use and the risk of endome-trial cancer. JAMA, 257: 796-800, 1987.

76. Bertram, J. S., Kolonel, L. N., and Meyskens, F. L., Jr. Rationale andstrategies for chemoprevention of cancer in humans. Cancer Res., 47: 3012-3031, 1987.

77. Kates, R. W. Success, strain, and surprise. Issues Sci. Technol., 3: 46-58,1985.

78. National Research Council. Regulating Pesticides in Foods. The DelaneyParadox. Washington, DC: National Academy Press, 1987.

79. National Cancer Institute. Cancer Control Objectives for the Nation: 1985-2000. National Cancer Institute Monographs No. 2. Washington, DC:United States Department of Health and Human Services, 1986.

80. Food and Drug Administration. Listing of D&C Orange No. 17 for use inexternally applied drugs and cosmetics. Fed. Regist., 51 (152): 28331-28364,1986.

81. The Conservation Foundation. Risk Assessment and Risk Control. Washington, DC: The Conservation Foundation, 1985.

82. Holland, J. F. The cancer breakthrough myth. Mt. Sinai J. Med., 44: 674-681, 1977.

83. National Panel of Consultants on the Conquest of Cancer. National Programfor the Conquest of Cancer. Washington, DC: United States GovernmentPrinting Office, 1971.

84. Miller. E. C. Some current perspectives on chemical carcinogenesis in humans and experimental animals: Presidential address. Cancer Res., 38:1479-1496, 1978.

85. Shear, M. J. Invasion of the ivory towerâ€”The AACR faces its second halfcentury: Presidential address. Cancer Res., 29: 1319-1324, 1969.

86. Epstein, Samuel, S. Losing the War Against Cancer: Who's to Blame andWhat To Do About It-A Position Paper on the Politics of Cancer, 1987.Congressional Record E3449-E3454, 1987.

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1988;48:1381-1389. Cancer Res John Higginson CarcinogenesisImplications for Future Research in Environmental Changing Concepts in Cancer Prevention: Limitations and

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[CANCER RESEARCH 48, 1381-1389, March 15, 1988 ......difficult and slow, represents the most logical alternative. This will require long-term major investments in fundamental research