Monthly Archives: January 2005

Risk, cancer and manmade chemicals

  • 1/30/2005
  • Bruce Ames and Lois Swirsky Gold
  • “Cancer Prevention and the Environmental Chemical Distraction”

This is an edited version of a chapter titled ‘Cancer Prevention and the Environmental Chemical Distraction’, by Bruce Ames and Lois Swirsky Gold, in Politicizing Science: the Alchemy of Policymaking, Michael Gough ed., Hoover Institute Press, Stanford, California (2003).

Blaming synthetic chemicals for a ‘cancer epidemic’ is flawed science that makes for dubious policy.

Entering a new millennium seems a good time to challenge some old ideas about cancer cause and prevention, which in our view are implausible, have little supportive evidence, and might best be left behind. In this essay, we summarise data and conclusions from 15 years of work, raising five issues that involve toxicology, nutrition, public health, and US government regulatory policy:

1. There is no cancer epidemic other than that due to smoking.

2. The dose makes the poison. Half of all chemicals tested, whether natural or synthetic, cause cancer in high-dose rodent cancer tests. Evidence suggests that this high rate is due primarily to effects that are unique to high doses. The results of these high-dose tests have been used to regulate low-dose human exposures, but are not likely to be relevant.

3. Even Rachel Carson was made of chemicals: natural v synthetic chemicals. Human exposure to naturally occurring rodent carcinogens is ubiquitous and dwarfs the exposure of the general public to synthetic rodent carcinogens.

4. Errors of omission. The major causes of cancer (other than smoking) do not involve exposures to exogenous chemicals that cause cancer in high-dose tests; rather, the major causes are dietary imbalances, hormonal factors, infection and inflammation, and genetic factors. Insufficiency of many vitamins and minerals, which is preventable by supplementation, causes DNA damage by a mechanism similar to radiation.

5. Damage by distraction: regulating low hypothetical risks. Regulatory policy places unwarranted emphasis on reducing low-level exposures to synthetic chemicals. Putting large amounts of money into small hypothetical risks can damage public health by diverting resources and distracting the public from major risks.

The dose makes the poison

The main rule in toxicology is that ‘the dose makes the poison’. At some level, every chemical becomes toxic, but there are safe levels below that.

In contrast to that rule, a scientific consensus evolved in the 1970s that we should treat carcinogens differently, that we should assume that even low doses might cause cancer, even though we lacked the methods for measuring carcinogenic effects at low levels. In large part, this assumption was based on the idea that mutagens – chemicals that cause changes in DNA – are carcinogens and that the risk of mutations was directly related to the number of mutagens introduced into a cell. It was also assumed that: 1. only a small proportion of chemicals would have carcinogenic potential; 2. testing at a high dose would not produce a carcinogenic effect unique to the high dose; and 3. carcinogens were likely to be synthetic industrial chemicals. It is time to take account of information indicating that all three assumptions are wrong.

Laws and regulations directed at synthetic chemicals got a big push from the widely publicised ‘cancer epidemic’, which supposedly stemmed from exposures to those chemicals. In fact, there is not now and there never was a cancer epidemic, and cancer mortality, excluding lung cancer mortality, has declined by 19 percent since 1950 (1). Lung cancer mortality began dropping around 1990 as a result of reduced smoking rates, and that trend is likely to continue. Regardless of the absence of evidence for a cancer epidemic, the ‘epidemic’ has left a long-lasting legacy – a regulatory focus on synthetic chemicals.

About 50 percent of chemicals, both natural and synthetic, that have been tested in standard, high-dose, animal cancer tests are rodent carcinogens (Table 1) (2). What explains the high percentage? In standard cancer tests, rodents are given a near-toxic dose of the test substance over their lifetime, the maximum tolerated dose (MTD), to maximise the chance of detecting any carcinogenicity. Evidence is accumulating that cell division caused by the high dose itself, rather than the chemical per se, contributes to cancer in these tests (3).

High doses can cause chronic wounding of tissues, cell death, and consequent chronic cell division of neighbouring cells, which would otherwise not divide. Cell division is a risk factor for cancer because there is some probability that a mutation will occur each time DNA is replicated, and some of those mutations can lead to cancer. A high proportion (41 percent) of chemicals that are carcinogens in rodent tests are not mutagenic, and their carcinogenicity may result from cell killing and consequent division at the high doses tested. Such increased cell division does not occur at the low levels of synthetic chemicals to which humans are usually exposed.

Defenders of rodent tests argue that the high rate of positive tests results from selecting more suspicious chemicals to test, and this seems a likely bias because cancer testing is both expensive and time-consuming, making it prudent to test suspicious compounds. One argument against such a selection bias is the high rate of positive tests for drugs (Table 1) because drug development favours chemicals that are not mutagens or expected carcinogens (4).

A second argument against selection bias is that the knowledge needed to predict carcinogenicity in rodent tests is highly imperfect, even now, after decades of test results have become available on which to base predictions. For example, in 1990 there was wide disagreement among experts about which chemicals would be carcinogenic when subsequently tested by the US National Toxicology Program (5). Moreover, if the primary basis for selection of chemicals to test were suspicion of carcinogenicity, selection would focus on mutagens (80 percent are carcinogenic compared to 50 percent of nonmutagens). In fact, a majority of tested chemicals, 55 percent, are nonmutagens.

It seems likely that a high proportion of all chemicals, whether synthetic or natural, would be ‘carcinogens’ if administered in the standard rodent bioassay at the MTD, primarily because of the effects of high doses on cell death and division and DNA damage and repair (6). Without additional data about how a chemical causes cancer, the interpretation of a positive result in a rodent bioassay is highly uncertain. The induction of cancer could be the result of the high doses tested and have no predictive value about what might occur at lower doses.

The processes of mutagenesis and carcinogenesis are complicated because of many factors, which are dose-dependent (7). For instance, normal cells contain an appreciable level of DNA lesions, and they contain enzymes that repair the lesions with high efficiency (8). The number of those lesions increases in tissues injured by high doses of chemicals (9) and may overwhelm the capacity of the repair enzymes. The far lower levels of chemicals to which humans are exposed through water pollution or synthetic pesticide residues on food are not sufficient to increase the number of DNA lesions in any appreciable way and may pose no or minimal cancer risks.

Regulatory agencies do not consider the great uncertainties in extrapolating from the effects observed in high-dose rodent tests to predictions of possible effects in humans at far lower doses. Instead, they assume that the effects are directly proportional to dose – that there is a linear relationship between dose and cancer – and they calculate the ‘virtually safe dose’ (VSD), which corresponds to a maximum, hypothetical risk of one additional cancer in a million exposed people, and set the VSD as the acceptable exposure level. To the extent that high doses of nonmutagens are the cause of carcinogenicity in rodent bioassays, the linear model is inappropriate (10).

Linearity of dose response seems unlikely in any case even for chemicals that are mutagens because of the inducibility of the numerous defence enzymes that deal with the thousands of exogenous chemicals that we encounter in our diets, and protect us against the natural world of mutagens as well as the small amounts of synthetic chemicals (11).

Regulatory agencies are moving to take nonlinearity and questions about mechanisms of carcinogenicity into account; for example, the US Environmental Protection Agency (EPA) recently concluded that chloroform (a by-product of disinfecting water with chlorine) was not likely to be carcinogenic to humans unless the exposures were high enough to cause cell toxicity and increased cell division. The chloroform levels in drinking water are low and do not produce such effects (12).

Even Rachel Carson was made of chemicals: Natural v synthetic chemicals

About 99.9 percent of the chemicals humans ingest are natural, and the amounts of synthetic pesticide residues in foods are insignificant compared to the amount of natural pesticides that are always in our diet because of the plants we eat (13). Of all dietary pesticides that humans eat, 99.99 percent are natural chemicals produced by plants to defend themselves against fungi, insects, and other animal predators. The natural pesticides come in great variety because each plant produces a different array of such chemicals.

We have estimated that on average Americans ingest roughly 5,000 to 10,000 different natural pesticides and their breakdown products. Each day, the average American eats about 1,500 milligrams (mg = 1/1000th of a gram) of natural pesticides, which is about 10,000 times more than the 0.09 mg they consume of synthetic pesticide residues (14).

Only a small proportion of natural pesticides have been tested for carcinogenicity, but 38 of the 72 tested are rodent carcinogens. As shown in Table 2, naturally occurring pesticides that are rodent carcinogens are ubiquitous in common fruits, vegetables, herbs, and spices. The widespread distribution of such chemicals means that no diet can be free of natural chemicals that are rodent carcinogens.

The average American eats about 2,000 mg of burnt material, which is produced in usual cooking practices, each day. That burnt material contains many rodent carcinogens and mutagens, swamping, again, the 0.09 mg of 200 synthetic chemicals, primarily synthetic pesticides, that are ingested each day and that are classified as rodent carcinogens.

The natural chemicals that are known rodent carcinogens in a single cup of coffee are about equal in weight to a year’s worth of ingested synthetic pesticide residues that are rodent carcinogens. This is so, even though only three percent of the natural chemicals in roasted coffee have been adequately tested for carcinogenicity (Table 3). This does not mean that coffee or natural pesticides are dangerous; rather, assumptions about high-dose animal cancer tests for assessing human risk at low doses need re-examination.

Ranking risks

Gaining a broad perspective about the vast number of chemicals to which humans are exposed can be helpful when setting research and regulatory priorities. Rodent cancer tests by themselves provide little information about how a chemical causes cancer or about low-dose risk. The assumption that synthetic chemicals are hazardous has led to a bias in testing, and such chemicals account for 76 percent (451 of 590) of the chemicals tested chronically in both rats and mice (Table 1). The world of natural chemicals has never been tested systematically.

One reasonable strategy to use the available information about cancer risk is to construct an index to compare and rank possible carcinogenic hazards from a wide variety of chemical exposures at levels typically experienced by humans, and then to focus research and regulatory efforts on those that rank highest (15).

Although one cannot say whether the ranked chemical exposures are likely to be of major or minor importance in human cancer, it is not prudent to focus attention on risks at the bottom of a ranking if the same methodology identifies numerous, common human exposures that pose much greater possible risks. Our rankings are based on the human exposure/rodent potency (HERP) index, which is the ratio between the average human exposure to a chemical and the dose that caused cancer in 50 percent of exposed rodents.

Overall, our analyses have shown that HERP values for some historically high exposures in the workplace – to butadiene and tetrachloroethylene – and to some pharmaceuticals -clofibrate – rank high, and that there is an enormous background of naturally occurring rodent carcinogens in typical portions of common foods. The background of natural exposures casts doubt on the relative importance of low-dose exposures to residues of synthetic chemicals such as pesticides. (A committee of the National Research Council of the National Academy of Sciences reached similar conclusions about natural v synthetic chemicals in the diet, and called for further research on natural chemicals.) (16)

The possible carcinogenic hazards from synthetic pesticides are minimal compared to the background of nature’s pesticides, though neither may be a hazard at the low doses consumed. Analysis also indicates that many ordinary foods would not pass the regulatory criteria used for synthetic chemicals. Caution is necessary in drawing conclusions about the occurrence in the diet of natural chemicals that are rodent carcinogens. These dietary exposures are not necessarily of much relevance to human cancer. The data call for a reevaluation of the utility of animal cancer tests in protecting the public against minor hypothetical risks without understanding how the chemical causes tumours.

Cellular defences against chemical carcinogens work against natural and synthetic chemicals

It is often assumed that because natural chemicals are part of human evolutionary history, whereas synthetic chemicals are recent, the mechanisms evolved in animals to cope with the toxicity of natural chemicals will fail to protect against synthetic chemicals. This assumption is flawed for several reasons.

1. Human defences to ward off effects of exposures to toxins are usually general, directed at classes of similar chemicals, rather than tailored for specific chemicals, and they work against both natural and synthetic chemicals (17). Examples of general defences include the continuous shedding of cells exposed to toxins. The surface layers of the mouth, esophagus, stomach, intestine, colon, skin, and lungs are discarded every few days; DNA repair enzymes repair DNA damage regardless of the source of the damage. Detoxification enzymes of the liver and other organs generally react with classes of chemicals rather than individual chemicals.

General defence mechanisms make good evolutionary sense for animals, such as humans, which eat plants and encounter a diverse and ever-changing array of plant toxins in an evolving world. A herbivore that had defences against only a specific set of toxins would be at great disadvantage in obtaining new food when favoured foods became scarce or evolved new chemical defences.

2. Various natural toxins, which have been present throughout vertebrate evolutionary history, nevertheless cause cancer in vertebrates. Mould toxins, such as aflatoxin, have been shown to cause cancer in rodents (Table 1) and other species including humans. Many common elements are carcinogenic to humans at high doses – for example, salts of cadmium, beryllium, nickel, chromium, and arsenic, despite their presence throughout evolution. Furthermore, epidemiological studies from various parts of the world show that certain ingested natural substances may be carcinogenic risks to humans. Naturally occurring arsenic in drinking water causes cancer of the lung, bladder, and skin (18), and the chewing of betel nut with tobacco causes oral cancer.

3. Humans have not had time to evolve a ‘toxic harmony’ with all of their dietary plants.The human diet has changed markedly in the past few thousand years. Indeed, very few of the plants that humans eat today, such as coffee, cocoa, tea, potatoes, tomatoes, corn, avocados, mangoes, olives, and kiwi fruit, would have been present in a hunter-gatherer’s diet. Natural selection works far too slowly for humans to have evolved specific resistance to the food toxins in these newly introduced plants.

4. DDT is often viewed as the typically dangerous synthetic pesticide because it concentrates in adipose tissues and persists for years. DDT, the first synthetic pesticide, eradicated malaria from many parts of the world, including the USA. It was effective against many vectors of disease such as mosquitoes, tsetse flies, lice, ticks, and fleas and against many crop pests, significantly increasing the supply and lowering the cost of food, making fresh, nutritious foods more accessible to poor people. DDT was also of low toxicity to humans. DDT prevented many millions of deaths due to malaria (19).

There is no convincing epidemiological evidence (20), nor is there much toxicological plausibility, that the levels of DDT normally found in the environment or in human tissues are likely to be a significant contributor to cancer. Two chemical properties of DDT were important in focusing attention on it. DDT, once ingested, is stored in fatty tissues, and the DDT in an insect, when eaten by a small bird, will be concentrated and stored in the bird’s fat. If a larger bird, such as an eagle, eats the small bird, it will ingest the concentrated DDT and each additional meal of DDT-containing prey will increase the concentration. The chlorine components (substituents) of DDT cause it to be resistant to degradation in nature, and, as a result, it persists longer than most chemicals. Few synthetic chemicals share these properties.

These properties are not unique to synthetic chemicals. Many thousands of chlorinated chemicals are produced in nature (21), and natural pesticides can bioconcentrate if they are fat-soluble. Potatoes, for example, contain solanine and chaconine, which are fat-soluble, neurotoxic, natural pesticides that can be detected in the blood of all potato eaters. High levels of these potato neurotoxins have been shown to cause birth defects in rodents (22), though they have not been tested for carcinogenicity.

5. Because no plot of land is immune to attack by insects, plants need chemical defences – either natural or synthetic – to survive, and trade-offs between naturally occurring and synthetic pesticides are possible. One consequence of disproportionate concern about synthetic pesticide residues is that some plant breeders develop plants to be more insect-resistant, which sometimes increases their levels of natural pesticides, which can bring its own hazards.When a major grower introduced a new variety of highly insect-resistant celery into commerce, people who handled the celery developed rashes when they went out into the sunlight. Some detective work found that the pest-resistant celery contained 6,200 parts per billion (ppb) of carcinogenic (and mutagenic) psoralens instead of the 800 ppb present in common celery (23).

Errors of omission

High consumption of fruits and vegetables is associated with a lowered risk of degenerative diseases including cancer, cardiovascular disease, cataracts and brain dysfunction (24). More than 200 studies in the epidemiological literature show, with consistency, an association between low consumption of fruits and vegetables and high cancer incidence (Table 4). The evidence of a protective effect of fruits and vegetables is most convincing for cancers of the oral cavity, esophagus, stomach, and lung. The median relative risk of cancer of the lung, larynx, oral cavity, esophagus, stomach, bladder, pancreas, and cervix was about double for the quarter of the population with the lowest dietary intake of fruits and vegetables when compared to the quarter with the highest intake (25). The median relative risk, although elevated, was not as high for the hormonally related cancers of breast, prostate, and ovary, or for the colon.

Inadequate diets, with too few fruits and vegetables, are common. Fully 80 percent of children and adolescents (26) and 68 percent of adults (27) do not eat the five servings of fruits and vegetables per day recommended by the US National Cancer Institute and the National Research Council. Publicity about hundreds of minor hypothetical risks, such as pesticide residues, can cause a loss of perspective about what is important. In a survey, half the US public did not name fruit and vegetable consumption as protective against cancer (28).

Laboratory studies of vitamin and mineral inadequacy associate such deficiencies with DNA damage, which indicates that the vitamin and mineral content of fruits and vegetables may explain the observed association between fruit and vegetable intake and cancer risk. Antioxidants such as vitamin C (whose dietary source is fruits and vegetables), vitamin E, and selenium protect against oxidative damage caused by normal metabolism (29), smoking (30), and inflammation (31).

Laboratory evidence ranging from likely to compelling indicates that deficiency of some vitamins and minerals – folic acid, vitamins B12, B6, C, and E, niacin, iron, and zinc – causes damage to DNA that mimics the damage caused by radiation (32). In the USA, the percentage of the population that consumes less than half the Recommended Daily Allowance (RDA) in the diet (that is, ignoring supplement use) for five of these eight vitamins or minerals is estimated to be: zinc (10 percent of women/men older than 50), iron (25 percent of menstruating women, and 5 percent of women over 50), vitamin C (25 percent of women/men), folate (50 percent of women; 25 percent of men), vitamin B6 (10 percent of women/men), vitamin B12 (10 percent of women; 5 percent of men) (33).

Folic acid (or folate) deficiency, one of the most common vitamin deficiencies in the population consuming few dietary fruits and
vegetables, causes chromosome breaks in humans (34), analogous to those caused by radiation. Folate supplementation above the RDA has been shown to minimise chromosome breakage (35). Researchers conducting a long-term study of women’s health, the Nurses’ Health Study, associated folate deficiency with increased risk of colon cancer (36). They also reported that women who took a multivitamin supplement containing folate for 15 years had a 75 percent lower risk of colon cancer (37). Folate deficiency also damages human sperm (38), causes neural tube defects in the fetus, and an estimated 10 percent of USA heart disease (39).

Approximately 10 percent of the US population (40) had a lower folate level than that at which chromosome breaks occur (41). The recent decision in the United States to supplement flour, rice, pasta, and cornmeal with folate (42) may reduce the percentage of the population with the deficiency.

Other vitamins – vitamin B6 and niacin – complement folic acid. Vitamin B6 deficiency apparently causes chromosome breaks by the same mechanism as folate deficiency (43). Niacin is important to the repair of DNA strand-breaks (44). As a result, dietary insufficiencies of niacin (15 percent of some populations are deficient) (45), folate, vitamin B6, and antioxidants, such as vitamin C, may interact synergistically to adversely affect DNA synthesis and repair.

People with diets deficient in fruits and vegetables generally have vitamin and mineral deficiencies. The findings summarised in Table 4, which associate higher cancer rates with such diets, underline the importance of fruits and vegetables and the vitamins and minerals they contain in cancer prevention.

Vitamins and minerals, whose main dietary sources are other than fruits and vegetables, are also likely to play a significant role in the prevention and repair of DNA damage, and thus are important to the maintenance of long-term health. Vitamin B12 is found in animal products, and deficiencies of B12 cause a functional folate deficiency, accumulation of the amino acid homocysteine (a risk factor for heart disease) (46), and chromosome breaks. B12 supplementation above the RDA was necessary to minimise chromosome breakage (47). Strict vegetarians are at increased risk for developing vitamin B12 deficiency.

Epidemiological studies of supplement usage (vitamin and mineral intake by pill) have shown at most only modest support for an association between intake of these substances and lower cancer rates. Many problems complicate those studies, including the difficulty in measuring supplement use over a long period of time, and potential confounding of supplement usage with many other aspects of a healthy lifestyle that are related to it, such as more exercise, better diet, and not smoking. Clinical trials of supplements are generally too short to measure cancer risk, since cancers usually develop slowly and the risk increases with age; moreover, such trials cannot measure the potential reduction in risk if supplements are taken throughout a lifetime.

Additionally, cancer risks of supplement users may be overestimated because they are more likely to undergo early screening like mammograms or tests for prostate cancer, which are associated with increased diagnosis rates, and can artificially increase the apparent incidence rate. Such confounding factors are not measured in many epidemiological studies.

The strongest effect in clinical trials was for a protective effect of vitamin E against cancers of the prostate and colon (48). More well-done trials will increase the information about the usefulness of supplements in cancer prevention. In the meantime, it is clear that intake of adequate amounts of vitamins and minerals may have a major effect on health, and the costs and risks of a daily multivitamin/mineral pill are low (49). More research in this area, as well as efforts to improve diets, should be high priorities for public policy.

Damage by distraction: Regulating low hypothetical risks

Synthetic chemicals that mimic hormones – ‘environmental estrogens’ or ‘endocrine disruptors’ – arose as a major environmental issue in the 1990s. Environmental concerns have focused on exposures to estrogenic organochlorine residues (largely plastics and pesticides) that are tiny compared to the normal dietary intake of naturally occurring endocrine-active chemicals in fruits and vegetables (50). These low levels of human exposure to the synthetic chemicals seem toxicologically implausible as a significant cause of cancer or of reproductive abnormalities.

Recent epidemiological studies have found no association between organochlorine pesticides and breast cancer, including one in which DDT, DDE, dieldrin, and chlordane were measured in blood of women on Long Island (51). Synthetic hormone mimics have been proposed as a cause of declining sperm counts, even though it has not been shown that sperm counts are declining (52). An analysis of US data about sperm counts found distinct geographical differences, with the highest concentrations in New York City (53). When geographic differences were taken into account, there was no significant change in sperm counts for the past 50 years.

Some recent studies have compared estrogenic equivalents (EQ) of dietary intake of synthetic chemicals v phytoestrogens (estrogens of plant origin) in the normal diet, by considering both the amounts consumed by humans and estrogenic potency. Results support the idea that synthetic residues are orders of magnitude lower in EQ and are generally weaker in potency. Scientists using a series of in vitro assays calculated the EQs in 200 ml of Cabernet Sauvignon wine and the EQs from average daily intake of organochlorine pesticides (54). EQs in a single glass of wine were about 1,000 times higher (55).


Because there is no risk-free world and resources are limited, society must set priorities based on cost-effectiveness in order to save the most lives (56). The EPA projected in 1991 that the cost to society of US environmental regulations in 1997 would be about US$140 billion per year (about 2.6 percent of gross national product) (57). Most of this cost is borne by the private sector, which passes much of it along to consumers in higher prices.

Several economic analyses have concluded that current expenditures are not cost-effective; that is, resources are not used so as to save the most lives per dollar. One estimate is that the USA could prevent 60,000 deaths per year by redirecting the same dollar resources to more cost-effective programmes (58). For example, the median toxin control programme, such as those administered by EPA, costs 146 times more per year of life saved than the median medical intervention programme. The true difference is likely to be greater, because cancer risk estimates for toxin control programmes are worst-case, hypothetical estimates, and there may be no risk at low dose. Rules on air and water pollution are necessary (for example, it was a public health advance to phase lead out of gasoline), and clearly, cancer prevention is not the only reason for regulations.

The many worst-case assumptions built into cancer risk assessments are there because of policy decisions, not because of scientific ones, and they confuse attempts to allocate money effectively for public health. For example, EPA estimates of synthetic pesticide residues in the diet have used the theoretical maximum human residue that is anticipated under the most severe field application conditions, which is often a large overestimate compared to the measured residues in food. Despite the EPA’s estimated high risks from exposures to several pesticides, the US Food and Drug Administration detected no residues of those pesticides in the food samples in its Total Diet Study (59).

Regulatory efforts to reduce low-level human exposures to synthetic chemicals because they are rodent carcinogens are expensive, can do nothing but reduce already minuscule chemical concentrations, and are unlikely to have any effect on cancer rates. Moreover, they distract from the major task of improving public health through increasing scientific understanding about how to prevent cancer, and increasing public understanding of how lifestyle influences health.

(1) L. A. G. Ries et al., SEER Cancer Statistics Review, 1973-1997 (Bethesda, Md.: National Cancer Institute, 2000).

(2) L. S. Gold et al., Misconceptions About the Causes of Cancer, L. S. Gold and E. Zeiger, eds., Handbook of Carcinogenic Potency and Genotoxicity Databases (Boca Raton, Fla.: CRC Press, 1997); L. S. Gold et al., ‘Supplement to the Carcinogemic Potency Database (CPDB): Results of Animal Bioassays Published in the General Literature in 1993-1994 and by the National Toxi- cology Programin 1995-1996,’ Environ. Health Perspect. 107 (Suppl. 4, 1999): 527-600.

(3) B. N. Ames and L. S. Gold, ‘Chemical Carcinogenesis: Too Many Rodent Carcinogens,’ Proc. Natl. Acad. Sci. U.S.A. 87 (1990): 7772-76; S. M. Cohen, ‘Cell Proliferation and Carcinogenesis,’ Drug Metab. Rev. 30 (1998): 339-57.

(4) See L. S. Gold, T. H. Slone, and B. N. Ames, ‘What Do Animal Cancer Tests Tell Us About Human Cancer Risk?: Overview of Analyses of the Carcinogenic Potency Database,’ Drug Metab. Rev. 30 (1998): 359-404.

(5) G. S. Omenn, S. Stuebbe, and L. B. Lave, ‘Predictions of Rodent Carcinogenicity Testing Results: Interpretation in Light of the Lave-Omenn Value-of-Information Model,’ Mol. Carcinog. 14 (1995): 37-45.

(6) B. Butterworth, R. Conolly, and K. Morgan, ‘A Strategy for Establishing Mode of Action of Chemical Carcinogens as a Guide for Approaches to Risk Assessment,’ Cancer Lett. 93 (1995): 129-46.

(7) J. G. Christensen, T. L. Goldsworthy,and R. C. Cattley, ‘Dysregulation of Apoptosis by C-myc in Transgenic Hepatocytes and Effects of Growth Factors and Nongenotoxic Carcinogens,’ Mol. Carcinog. 25 (1999): 273-84.

(8) H. J. Helbock et al., ‘DNA Oxidation Matters: The HPLC-EC Assay of 8-oxo-deoxyguanosine and 8-oxo-guanine,’ Proc. Natl. Acad. Sci. U.S.A. 95 (1998): 288-93.

(9) D. L. Laskin and K. J. Pendino, ‘Macrophages and Inflammatory Mediators in Tissue Injury,’ Annu. Rev. Pharmacol. Toxicol. 35 (1995): 655-77.

(10) D. W. Gaylor and L. S. Gold, ‘Regulatory Cancer Risk Assessment Based on a Quick Estimate of a BenchmarkDose Derivedfrom theMaximum Tolerated Dose,’ Regul. Toxicol. Pharmacol. 28 (1998): 222-25.

(11) T. D. Luckey, ‘Nurture with Ionizing Radiation: A Provocative Hypothesis,’ Nutr. Cancer 34 (1999): 1-11; Ames and Gold, ‘Paracelsus to Parascience.’

(12) U.S. Environmental Protection Agency, ‘Integrated Risk Information System (IRIS)’ (Cincinnati: Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, 2002).

(13) B. N. Ames, M. Profet, and L. S. Gold, ‘Nature’s Chemicals and Synthetic Chemicals: Comparative Toxicology,’ Proc. Natl. Acad. Sci. U.S.A. 87 (1990): 7782-86; B. N. Ames, M. Profet, and L. S. Gold, ‘Dietary Pesticides 99.99 Percent All Natural,’ ibid., 7777-81; L. S. Gold, T. H. Slone, and B. N. Ames, ‘Prioritization of Possible Carcinogenic Hazards in Food,’ in D. Tennant, ed., Food Chemical Risk Analysis (London: Chapman & Hall, 1997), pp. 267-95.

(14) E. L. Gunderson, ‘Chemical Contaminants Monitoring: FDA Total Diet Study, April 1982-April 1984, Dietary Intakes of Pesticides, Selected Elements, and Other Chemicals,’ J. Assoc. Off. Anal. Chem. 71 (1988):1200- 9.

(15) L. S. Gold et al., MisconceptionsAbout the Causes of Cancer; B. N. Ames, R. Magaw, and L. S. Gold, ‘Ranking Possible Carcinogenic Hazards,’ Science 236 (1987): 271-80.

(16) National Research Council, Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances (Washington, D.C.: National Academy Press, 1996).

(17) Ames, Profet, and Gold, ‘Nature’s Chemicals and Synthetic Chemicals.’ 18. National Research Council, Arsenic in Drinking Water: 2001 Update (Washington, D.C.: National Academy Press, 2001).

(19) National Academy of Sciences, U.S.A., The Life Sciences: Recent Progress and Application to Human Affairs, the World of Biological Research, Requirement for the Future (Washington, D.C.: Committee on Research in the Life Sciences, 1970).

(20) T. Key and G. Reeves, ‘Organochlorines in the Environment and Breast Cancer,’ Br. Med. J. 308 (1994): 1520-21.

(21) G. W. Gribble, ‘The Diversity of Natural Organochlorines in Living Organisms,’ Pure Appl. Chem. 68 (1996): 1699-1712.

(22) Ames, Profet, and Gold, ‘Nature’s Chemicals and Synthetic Chemicals.’

(23) S. F. Berkley et al., ‘Dermatitis in Grocery Workers Associated with High Natural Concentrations of Furanocoumarins in Celery,’ Ann. Intern. Med. 105 (1986): 351-55. (24) B. N. Ames, L. S. Gold, and W. C. Willett, ‘The Causes and Prevention of Cancer,’ Proc. Natl. Acad. Sci. U.S.A. 92 (1995): 5258-65; B. N. Ames, M. K. Shigenaga, and T. M. Hagen, ‘Oxidants, Anti-Oxidants, and the Degenerative Diseases of Aging,’ ibid. 90 (1993): 7915-22.

(25) G. Block, B. Patterson, and A. Subar, ‘Fruit, Vegetables, and Cancer Prevention: A Review of the Epidemiologic Evidence,’ Nutr. Cancer 18 (1992): 1-29.

(26) S. M. Krebs-Smith et al., ‘Fruit and Vegetable Intakes of Children and Adolescents in the United States,’ Arch. Pediatr. 150 (1996): 81-86.

(27) S. M. Krebs-Smith et al., ‘U.S. Adults’ Fruit and Vegetable Intakes, 1989 to 1991: A Revised Baseline for the Healthy People 2000 Objective,’ Am. J. Public Health 85 (1995): 1623-29.

(28) National Cancer Institute Graphic, ‘Why Eat Five?’ J. Natl. Cancer Inst. 88 (1996): 1314.

(29) H. J. Helbock et al.,’DNAOxidation Matters:TheHPLC-Electrochemical Detection Assay of 8-oxo-deoxyguanosine and 8-oxo-guanine,’ Proc. Natl. Acad. Sci. USA 95 (1998): 288-93.

(30) B. N. Ames, ‘Micronutrients Prevent Cancer and Delay Aging,’ Toxicol. Lett. 103 (1998): 5-18.

(31) Ames, Shigenaga, and Hagen, ‘Oxidants, Antioxidants, and the Degenerative Diseases of Aging.’

(32) Ames, ‘Micronutrients Prevent Cancer and Delay Aging.’

(33) B. N. Ames and P. Wakimoto, ‘Are Vitamin and Mineral Deficiencies a Major Cancer Risk?’ Nature Rev. Cancer 2 (2002): 694-704.

(34) B. C. Blount et al., ‘Folate Deficiency Causes Uracil Misincorporation into Human DNA and Chromosome Breakage: Implications for Cancer and Neuronal Damage,’ Proc. Natl. Acad. Sci. USA 94 (1997): 3290-95.

(35) M. Fenech, C. Aitken, and J. Rinaldi, ‘Folate, Vitamin B12, Homocysteine Status and DNA Damage in Young Australian Adults,’ Carcinogenesis 19 (1998): 1163-71.

(36) E. Giovannucci et al., ‘Folate, Methionine, and Alcohol Intake and Risk of Colorectal Adenoma,’ J. Natl. Cancer Inst. 85 (1993): 875-84.

(37) E. Giovannucci et al., ‘Multivitamin Use, Folate, and Colon Cancer in Women in the Nurses’ Health Study’ Ann. Intern. Med. 129 (1998): 517-24.

(38) L. M. Wallock et al., ‘Low Seminal Plasma Folate Concentrations Are Associated with Low Sperm Density and Count in Male Smokers and Nonsmokers,’ Fertil. Steril. 75 (2001): 252-59.

(39) C. J. Boushey et al., ‘A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease: Probable Benefits of Increasing Folic Acid Intakes,’ J. Am. Med. Assoc. 274 (1995): 1049-57.

(40) F. R. Senti and S. M. Pilch, ‘Analysis of Folate Data from the Second National Health and Nutrition Examination Survey (NHANES II)’ J. Nutr. 115 (1985): 1398-1402.

(41) Blount et al., ‘Folate Deficiency.’

(42) P. F. Jacques et al., ‘The Effect of Folic Acid Fortification on Plasma Folate and Total Homocysteine Concentrations,’ N. Engl. J. Med. 340 (1999): 1449-54.

(43) A. C. Huang, T. D. Shultz, and B. N. Ames, unpublished MS.

(44) J. Z. Zhang, S. M. Henning, and M. E. Swendseid, ‘Poly(ADP-ribose) Polymerase Activity and DNA Strand Breaks Are Affected in Tissues of Niacin- deficient Rats,’ J. Nutr. 123 (1993): 1349-55.

(45) E. L. Jacobson, ‘Niacin Deficiency and Cancer in Women,’ J. Am. Coll. Nutr. 12 (1993): 412-16.

(46) V. Herbert and L. J. Filer, Jr., ‘Vitamin B-12,’ in E. E. Ziegler, ed., Present Knowledge in Nutrition (Washington, D.C.: ILSI Press, 1996), pp. 191- 205.

(47) Fenech, Aitken, and Rinaldi, ‘Folate, Vitamin B12, Homocysteine Status and DNA Damage in Young Australian Adults.’

(48) R. E. Patterson, A. R. Kristal, and M. L. Neuhouser, ‘Vitamin Supplements and Cancer Risk: Epidemiologic Research and Recommendations,’ in A. Bendich and R. J. Deckelbau, eds., Primary and Secondary Preventive Nutrition (Totowa, N.J.: Humana Press, 2001), pp. 21-43.

(49) Ames and Wakimoto, ‘Are Vitamin and Mineral Deficiencies a Major Cancer Risk?’ (50) S. H. Safe, ‘Endocrine Disruptors and Human Health – Is There a Problem? An Update,’ Environ. Health Perspect. 108 (2000): 487-93.

(51) M. D. Gammon et al., ‘Environmental Toxins and Breast Cancer on Long Island. II. Organochlorine Compound Levels in Blood,’ Cancer Epidemiol. Biomarkers Prev. 11 (2002): 686-97.

(52) S. Becker and K. Berhane, ‘A Meta-analysis of 61 Sperm Count Studies Revisited,’ Fertil. Steril. 67 (1997): 1103-8; J. Gyllenborg et al., ‘Secular and Seasonal Changes in Semen Quality Among Young Danish Men: A Statistical Analysis of SemenSamplesfrom 1927 Donor Candidates During 1977-1995,’ Int. J. Androl. 22 (1999): 28-36; National Research Council, Hormonally Active Agents in the Environment (Washington, D.C.: National Academy Press, 1999); J. A. Saidi et al., ‘Declining Sperm Counts in the United States? A Critical Review,’ J. Urol. 161 (1999): 460-62; S. H. Swan, E. P. Elkin, and L. Fenster, ‘Have Sperm Densities Declined? A Reanalysis of Global Trend Data,’ Environ. Health Perspect. 105 (1997):1228-32.

(53) Saidi et al., ‘Declining Sperm Counts in the United States?’

(54) K. Gaido et al., ‘Comparative Estrogenic Activity of Wine Extracts and Organochlorine Pesticide Residues in Food,’ Environ. Health Perspect. 106 (Suppl. 6, 1998): 1347-51.

(55) National Research Council, Hormonally Active Agents in the Environment (Washington, D.C.: National Academy Press, 1999).

(56) R. W. Hahn, Risks, Costs, and Lives Saved: Getting Better Results from Regulation (New York: Oxford University Press and Washington, D.C.: AEI Press, 1996); J. Graham and J. Wiener, eds., Risk versus Risk: Tradeoffs in Protecting Health and the Environment (Cambridge, Mass.: Harvard University Press, 1995).

(57) U.S. Environmental Protection Agency, Environmental Investments: The Cost of a Clean Environment (Washington, D.C.: Office of the Administrator, 1991).

(58) T. O. Tengs et al., ‘Five Hundred Life-saving Interventions and Their Cost-effectiveness,’ Risk Anal. Prod. Safe Food 15 (1995): 369-89.

(59) L. S. Gold et al., ‘Pesticide Residues in Food: Investigation of Disparities in Cancer Risk Estimates,’ Cancer Lett. 117 (1997): 195-207; L. S. Gold et al., ‘Pesticide Residues in Food and Cancer Risk: A Critical Analysis,’ in Handbook of Pesticide Toxicology, 2d ed., ed. R. Krieger (San Diego: Academic Press, 2001), pp. 799-842.

OCF Note:
This article including tables is available at .

January, 2005|Archive|

Researcher says HPV vaccine may be a year away

  • 1/30/2005

Diane Harper, a researcher at Norris Cotton Cancer Center in Lebanon, N.H., has studied the link between human papillomavirus infection and cervical cancer for 20 years. Harper now believes she may have found a vaccine that protects against the two strains of HPV that are linked to 70% of cervical cancers. The vaccine, made by GlaxoSmithKline, was tested from 2000 to 2003 on 1,113 women ages 15 to 25 from the United States, Canada, and Brazil. In women who received three injections and follow-up testing, the vaccine was 100% effective. In those who received only one or two injections, the vaccine proved to be 91% effective. The vaccine offers protection for three to five years. No side effects, except for pain or redness at the injection site, were reported, said Harper, who added that she is an independent researcher and is not paid by GlaxoSmithKline.

“It offers such an advantage for women and such a change in health care, one that we will actually see in the next five years,” Harper said of the vaccine. If approved by the Food and Drug Administration, it could be available early next year. “I’m extremely excited about the possibilities.”

According to preliminary findings, said Harper, the vaccine may protect against HPV-associated diseases such as anal cancer, vaginal cancer, vulvular cancer, esophageal cancer, abnormal Pap smears, and mouth or oral cancer. “It’s going to take us 20 to 30 years to get the data, but we’re really hopeful this has long-term protective effects,” she said.

The vaccine is now in phase III trials–the final step before licensing the drug for general use–and involves 15,000 women worldwide. If approved, said Harper, the vaccine would be recommended for girls ages 10 to 12 with booster immunizations later. Harper and her research team also are examining an HPV vaccination for men, who often unknowingly carry the infection.

HPV is believed to be the most common sexually transmitted disease among gay men. Studies suggest that more than half of all sexually active gay men and as many as 90% of HIV-positive gay men carry HPV. The virus can cause anal or genital warts, and certain strains have been linked with an increased risk of anal cancer.

January, 2005|Archive|

Alcohol Listed as ‘Known Carcinogen’

  • 1/30/2005
  • U.S. Dept. of Health & Human Services:
  • Report on Carcinogens, 9th edition

For the first time alcoholic beverages have been listed as a known human carcinogen by the U.S. Department of Health and Human Services in its “Report on Carcinogens” 9th edition.

The report states that consumption of alcoholic beverages is causally related to cancers of the mouth pharynx larynx and esophagus and that studies indicate that the risk is most pronounced among smokers and at the highest levels of consumption.

The effect of a given level of alcoholic beverage intake on cancers of the head and neck is influenced by other factors, especially smoking, but that smoking does not explain the increased cancer hazard associated with alcoholic beverage consumption according to the report. There is evidence that suggests a link between alcoholic beverage consumption and cancer of the liver and breast.

Potential Hazard

The report was first ordered by Congress in 1978 to educate both the public and health professionals in the recognition that many cancers are apparently induced by chemicals in the home workplace general environment and from the use of certain drugs. It identifies “potential” cancer hazards.

A listing in the report does not by itself establish that a substance presents a cancer risk to an individual in daily life, according to press releases. However the “known” category is reserved for those substances for which there is sufficient evidence of carcinogenicity from studies in humans that indicates a cause and effect relationship between the exposure and human cancer.

Epidemiologic research has shown a dose-dependent association between alcohol consumption and certain types of cancer; as alcohol consumption increases, so does risk of developing certain cancers. Previous research indicated alcohol was a possible catalyst, but not a carcinogen itself.

January, 2005|Archive|

Lugol’s Dye Spray Chromoendoscopy Establishes Early Diagnosis of Esophageal Cancer in Patients with Primary Head and Neck Cancer

  • 1/27/2005
  • CL Hashimoto et al.
  • Am J Gastroenterol, February 1, 2005; 100(2): 275-82

Patients with primary head and neck cancer show a predisposition to develop esophageal cancer. The aim of this study was to investigate in these patients: the prevalence of esophageal cancer comparing the value of chromoendoscopy using Lugol’s solution examination to standard endoscopy, in the early diagnosis of esophageal cancer.

Prospective observational study at a state general university hospital in Sao Paulo, Brazil. 326 consecutive adult patients with primary head and neck cancer were evaluated. A standard endoscopy was performed, followed by a 2% lugol’s dye spray chromoendoscopy and histopathologic study. The prevalence of esophageal cancer was defined. The results of the two endoscopic methods were compared.

Twenty-four patients with esophageal cancer and high-grade intraepithelial neoplasia were detected and had a prevalence of 7.36%. Chromoendoscopy and standard endoscopy were equivalent to the diagnosis of advanced and invasive esophageal cancer. However, standard endoscopy diagnosed 55% of high-grade intraepithelial neoplasia, in comparison to chromoendoscopy that detected 100%.

Patients with primary head and neck cancer should be considered as high risks for the presence of esophageal cancer. Lugol’s dye chromoendoscopy diagnosed high-grade intraepithelial neoplasia, which went unnoticed with standard endoscopy. It permits a more exact detection of lesion boundaries and facilitates a more precise targeting of biopsy fragments.

CL Hashimoto, K Iriya, ER Baba, T Navarro-Rodriguez, MC Zerbini, JN Eisig, R Barbuti, D Chinzon, and JP Moraes-Filho

Authors’ affiliation:
Department of Gastroenterology, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil.

January, 2005|Archive|

Molecular profiling of tumor progression in head and neck cancer

  • 1/27/2005
  • TJ Belbin et al.
  • Arch Otolaryngol Head Neck Surg, January 1, 2005; 131(1): 10-8

To assess gene expression changes associated with tumor progression in patients with squamous cell carcinoma of the oral cavity.

A microarray containing 17 840 complementary DNA clones was used to measure gene expression changes associated with tumor progression in 9 patients with squamous cell carcinoma of the oral cavity. Samples were taken for analysis from the primary tumor, nodal metastasis, and “normal” mucosa from the patients’ oral cavity.

Tertiary care facility.Patients Nine patients with stage III or stage IV untreated oral cavity squamous cell carcinoma. RESULTS: Our analysis to categorize genes based on their expression patterns has identified 140 genes that consistently increased in expression during progression from normal tissue to invasive tumor and subsequently to metastatic node (in at least 4 of the 9 cases studied). A similar list of 94 genes has been identified that decreased in expression during tumor progression and metastasis. We validated this gene discovery approach by selecting moesin (a member of the ezrin/radixin/moesin [ERM] family of cytoskeletal proteins) and one of the genes that consistently increased in expression during tumor progression for subsequent immunohistochemical analysis using a head and neck squamous cell carcinoma tissue array.

A distinct pattern of gene expression, with progressive up- or down-regulation of expression, is found during the progression from histologically normal tissue to primary carcinoma and to nodal metastasis.

TJ Belbin, B Singh, RV Smith, ND Socci, VB Wreesmann, M Sanchez-Carbayo, J Masterson, S Patel, C Cordon-Cardo, MB Prystowsky, and G Childs

Authors’ Affiliation:
Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10461, USA

January, 2005|Archive|

Psychosocial effects in long-term head and neck cancer survivors

  • 1/27/2005
  • Richard L Holloway et al.
  • Head Neck, January 24, 2005

To identify and rate the importance of several psychosocial and physiologic influences on quality of life (QOL) among a cohort of 5-year head and neck cancer survivors, we conducted a cross-sectional study of a convenience sample that used both questionnaires and physiologic evaluations.

QOL was assessed by the Functional Assessment of Cancer Therapy (FACT) and the FACT Head and Neck additional concerns (FACT-H&N) questionnaires. Psychosocial characteristics (or risk factors) potentially influencing QOL were measured by the Millon Behavioral Health Inventory (MBHI) and the Social Support Questionnaire (SSQSR). Physiologic risk factors were measured in examinations that included shoulder and neck range of motion, whole and stimulated saliva measurements, and oropharyngeal swallowing efficiency. We evaluated the association of selected QOL measures with three groups of potential risk factors: psychosocial factors, consisting of selected MBHI and SSQSR scales; physiologic factors, consisting of selected physical ability measures; and a combination of psychosocial/physiologic factors.

The entire study population of 105 subjects completed the FACT and FACT-H&N questionnaires; 86 of these completed the physiologic tests as well. Combined psychosocial/physiologic models best predicted all QOL measures considered. Psychosocial models alone, compared with physiologic models alone, better predicted FACT physical and social/family well-being measures. Physiologic models alone, compared with psychosocial models alone, better predicted FACT-H&N additional concerns measures. Premorbid pessimism (MBHI) was consistently the best predictor of QOL measures.

Both psychosocial and physiologic factors influence QOL in patients with head and neck cancer, but many QOL measures are most strongly influenced by psychosocial considerations. Physicians and surgeons caring for long-term head and neck cancer survivors should be cognizant of the importance of psychosocial risk factors in the QOL of their patients.

Richard L Holloway, James L Hellewell, Anne M Marbella, Peter M Layde, Katherine B Myers, and Bruce H Campbell

Authors’ Affiliation:
Department of Family & Community Medicine, Medical College of Wisconsin

January, 2005|Archive|

Radiation Sensitizers: A Selective Review of Molecules Targeting DNA and Non-DNA Targets

  • 1/27/2005
  • Larry K. Kvols, MD
  • Society of Nuclear Medicine Jan 2005 as reported by

The ideal radiation sensitizer would reach the tumor in adequate concentrations and act selectively in the tumor compared with normal tissue. It would have predictable pharmacokinetics for timing with radiation treatment and could be administered with every radiation treatment. The ideal radiation sensitizer would have minimal toxicity itself and minimal or manageable enhancement of radiation toxicity. The ideal radiation sensitizer does not exist today. This review outlines the concept of combining 2 modalities of cancer treatment, radiation and drug therapy, to provide enhanced tumor cell kill in the treatment of human malignancies and discusses molecules that target DNA and non-DNA targets. Combining drugs that have unique mechanisms of action and absence of overlapping toxicities with systemically administered radiotherapy should be exploited in future clinical trials. This is an exciting time in clinical oncology research, because we have a plethora of new molecules to evaluate.

Surgery, radiation, and chemotherapy have been the mainstays of treatment for human malignancies for more than 40 years. The use of a combination of radiation and chemotherapy is often called chemoradiation in the medical literature. For most of the last 4 decades, this has involved the use of cytotoxic agents with external beam radiation. Recently, however, with newer molecules that target very specific pathophysiology or molecular pathways and the use of radiation delivered systemically by antibodies or hormones labeled with radionuclides, the concept of radiation sensitizers has been expanded.

Heidlberger’s preclinical studies in 1958 were the first to establish the concept of giving drugs concomitantly with radiation to enhance the effect of radiation (1). In the 1960s, Moertel et al. from the Mayo Clinic reported improved survival of patients with stomach and pancreatic cancer when the 2 modalities were combined (2). Initial reports showed only modest improvement; however, with a disease that had such a dismal prognosis, any improvement was welcome. In 1974, Nigro’s trial of 5-fluorouracil (FU) in combination with mitomycin C as concurrent therapy with radiation for cancer of the anal canal demanded the attention of both the radiation and medical oncology communities (3). Combined modality therapy is now well established in the following cancers: head and neck, esophagus, lung, stomach, pancreas, anal canal, and cervix (4- 14).

External beam radiation therapy and the combination of drugs and systemically administered radiation show interesting pharmacokinetic differences. Unlike drugs and systemically administered radiation, external beam radiation will penetrate tissue and cellular boundaries without any of the usual pharmacokinetic barriers. The dose delivered can be preplanned with external beam radiation and brachytherapy. Chemotherapy and radionuclides attached to carrier molecules, such as monoclonal antibodies or peptides, require distribution from the site of administration to the blood, tissue, interstitial space, cell, and subcellular target.

An ideal radiation sensitizer would reach the tumor in adequate concentrations and act selectively in the tumor compared with normal tissue. It would have predictable pharmacokinetics for timing with radiation treatment and could be administered with every radiation treatment. The ideal radiation sensitizer would have minimal toxicity itself and minimal or manageable enhancement of radiation toxicity. The ideal radiation sensitizer does not exist today.

This review will discuss the concept of combining 2 modalities of cancer treatment, radiation and drug therapy, to provide enhanced tumor cell kill in the treatment of human malignancies. These drugs may be traditional chemotherapeutic agents or some of the newer molecular targeting agents. Much of the published clinical research has reported on the traditional cytotoxic agents, nucleoside analogs and platinum compounds. Substantially more information is currently available from basic and clinical research with these agents in combination with standard external beam radiation therapy than with systemically administered therapy, such as radiolabeled peptides or radiolabeled monoclonal antibodies. The concepts, however, should be applicable in both arenas.

Some of the newer agents, such as growth factor inhibitors, cyclooxygenase enzyme 2 (COX-2) inhibitors, farnesyltransferase inhibitors, and inhibitors of new vessel formation, will also be reviewed in this paper.

How do conventional chemotherapy drugs bring about radiosensitization?


One of the first agents to be exploited as a radiation sensitizer was 5FU, and the basis for its action is currently thought to be primarily from thymidilate synthase inhibition (75). Interestingly, noncytotoxic concentrations of 5FU can also increase radiation sensitivity in vitro, but only when cells are incubated with drug before radiation. Because of the short half-life of 5FU in plasma, these laboratory studies have suggested that the drug should be given by continuous intravenous infusion (CIVI) during a course of fractionated radiation if radiosensitization of most fractions is to be achieved. In fact, the use of CIVI of 5FU with radiation has become the preferred therapy for both pancreatic and rectal cancer (16,17).

Of course, this approach requires long-term venous access and specialized pumps over 5-6 wk, which can predispose the patient to thrombosis or infection. An oral form of 5FU, the prodrug capecitabine, may prove to make the protracted combined modality therapy easier and safer in the clinic, but additional studies are necessary.

Analogs of Platinum

The platinum analogs include cisplatin, carboplatin, and oxaliplatin. These are used clinically in combination with radiation in a variety of solid tumors. When given before or after radiation, these analogs are believed to enhance cell killing by one of several mechanisms. These mechanisms include enhanced formation of toxic platinum intermediates in the presence of radiation-induced free radicals, inhibition of DNA repair, radiation-induced increase in cellular platinum uptake, and cell cycle arrest (18-22).

The concomitant use of cisplatin or carboplatin has been shown to improve clinical outcome for non-small lung cancer, cervical cancer, and cancers of the head and neck (23-25).

Oxaliplatin is a third-generation cisplatin analog that has recently been approved for use in colorectal cancer. Freyer et al. (26) have reported using oxaliplatin along with 5FU and folinic acid and concomitant radiation for rectal cancer. The Eastern Cooperative Oncology Group and Cancer and Leukemia Group B also have studies underway looking these same combinations in rectal cancer.


Gemcitabine is an analog of cytarabine (cytosine arabinoside) with a broad spectrum of clinical activity against human cancers, particularly pancreatic and non-small cell lung cancer (27-30). Gemcitabine is a potent radiosensitizer in both laboratory studies and clinical trials. In the laboratory, there was no evidence of radiosensitization when cells were radiated before gemcitabine exposure, and the greatest enhancement ratio was seen when cells were incubated for 24 h before irradiation (31), Maximum sensitization appears to require simultaneous redistribution into S phase along with deoxyadenosine triphosphate (dATP) pool depletion (32). The dATP pool depletion is a result of ribonucleotide reductase inhibition.

Minimally cytotoxic concentrations of gemcitabine can radiosensitize, and unlike 5FU, do not have to be given continuously. Clinical trials evaluating once- or twice-weekly gemcitabine along with radiation in head and neck cancer and pancreatic cancer are in process (33).

DNA Topoisomerase I-Targeting Drugs

The camptothecin derivatives, topotecan and irinotecan, target the topoisomerase enzyme. The activities of topoisomerase I are important for many aspects of DNA metabolism, including initiation and elongation of RNA transcription, DNA replication, and the regulation of DNA supercoiling, which is essential for maintaining the stability of the genome (34).

Drug interference with topoisomerse I-mediated cleavage rejoining of DNA strands is thought to be the common mechanism of action of these drugs. The presence of upregulated levels of topoisomerase in tumor cells compared with normal cells suggests a therapeutic advantage of topoisomerase I-targeting drugs selective against slow- growing as well as rapidly proliferating tumors.

Chen et al. (35) conducted clonogenic survival assays using cultured mammalian cells. They found that drug incubation with camptothecin derivatives radiosensitized log-phased human MCF-7 breast cancer cells in a schedule-dependent manner. The radiation sensitization effect was observed when the cells were exposed to drug treatment before or concurrent with radiation treatment but not after radiation treatment. The implication of these observations is that camptothecin derivatives should be administered before or concurrently with radiation to optimize the radiosensitizing effect during chemoradiation trials.

A wide \range of clinical antitumor activity, including activity against colorectal cancer, ovarian cancer, both small cell and non- small cell lung cancer, and malignant lymphomas, has been seen with the camptothecin derivatives. Based on clinical success as systemic therapy, chemoradiation trials are ongoing in a variety of solid tumors.

Molecules that are radiosensitizing but do not target DNA

Most of our chemotherapeutic agents and radiation therapy have focused on DNA as the target. Non-DNA targets may be effective in killing the cell or modifying the cell in such away that it is more susceptible to cell killing after radiation-induced damage.

Epidermal Growth Factor Receptor Blockade

The ErbB family is a group of 4 structurally similar growth factor receptors with tyrosine-kinase activity (epidermal growth factor receptor [EGFR], HER2/neu, ErbB-3, ErbB-4), which dimerize on binding with several ligands, including EGF and transforming growth factor (TGF), allowing downstream transduction of mitogenic signals. New agents developed to inhibit EGFR function include monoclonal antibodies and small-molecule receptor tyrosine-kinase inhibitors. In this review, the emphasis will be on results of in vivo and in vitro studies with the monoclonal antibody, C225 (cetuximab), and the tyrosine-kinase inhibitor CI-1033 (gefitinib, Iressa; AstraZeneca pic) as radiation sensitizers.

Squamous cell carcinomas (SCC) arising in the head and neck have high expression of EGFR. Overexpression of this receptor often accompanies growth and development of these malignant tumors. The anti-EGFR monoclonal antibody, C225, is a potent antiproliferative agent in these tumors. It is capable of inhibiting tumor cell growth kinetics. In addition, preclinical studies have demonstrated the capacity of C225 to enhance in vitro radiosensitivity and to promote radiation-induced apoptosis (36). In studies using a xenograft model system, human head and neck cancer cells are particularly sensitive to radiation damage when the EGFR signaling pathway in these cells is blocked by C225. Most impressively, the in vivo tumor response after combined administration of C225 and radiation was dramatic and long lasting. Such profound antitumor activity in vivo appeared to derive not only from proliferative growth inhibition (with associated cell cycle redistribution) but also from inhibition of postradiation damage repair and inhibition of tumor angiogenesis (37). Because locoregional dis ease recurrence remains the dominant form of treatment failure for these patients, the results of phase 3 clinical trials evaluating this approach are eagerly awaited.

Although C225 is a reversible inhibitor that exhibits receptor selectively, CI-1033 appears to bind to all tyrosinekinase receptors irreversibly and thus may have a larger spectrum of activity in the clinic.

Farnesyltransferase Inhibitors

Activation of Ras by mutation, overexpression, or signaling through tyrosine-kinase receptors is associated with radioresistance. It follows that therapies which inhibit Ras function could be effective means to radiosensitize certain solid tumors. Brunner et al. (38) used clonogenic assays with human and rodent tumor cell lines and transfected cell lines in the testing of radiosensitivity. Xenograft tumors were treated with farnesyltransferase inhibitors and radiation and assayed for ex vivo plating efficiency and regrowth of tumors. Blocking the prenylation of Ras proteins in cell lines with Ras activated by mutations or receptor signaling resulted in radiation sensitization in vitro and in vivo. The PI3 kinase downstream pathway was identified as a contributor to Ras-mediated radiation resistance. In a phase 1 trial of the farnesyltransferase inhibitor, L-778-123, in advanced head and neck cancer and non-small cell lung cancer, the same investigators demonstrated a high response rate coupled with mild toxicity (39).

COX-2 Inhibitors

Prostaglandins have been known to impact the radiosensitivity of cells and tissues, and many studies have centered on exploiting nonspecific prostaglandin inhibitors such as nonsteroidal antiinflammatory drugs for therapeutic gain. These studies have ultimately been unsuccessful because of a lack of targeted specificity against the tumor. The discovery of the inducible COX-2 and development of some highly selective inhibitors (which spare the constitutive COX-1 activity) have renewed excitement for modulating tumor prostaglandins as a method of specific radiosensitization of tumors, while at the same time sparing normal tissues (36). Celecoxib is the selective COX-2 inhibitor that has been studied in non-small cell lung cancer and in upper gastrointestinal tract cancers.

Targeting Tumor Vasculature

The progressive enlargement of a tumor mass requires the formation of new blood vessels to facilitate delivery of nutrients and oxygen. This process is called angiogenesis, and all types of solid tumor cells promote new blood vessel formation by releasing endothelial cell growth factors. Two critically important growth factors are basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). These support endothelial cell proliferation and migration of blood vessels.

Several approaches targeting bFGF and VEGF have been developed and include the use of antibodies such as bevazucimab and thalidomide. Bevazucimab has recently been approved for use in colorectal cancer, and thalidomide has been shown to have activity in Kaposi’s sarcoma, multiple myeloma, prostate cancer, and islet cell carcinomas.

Some investigators have expressed concern that inhibition of tumor angiogenesis could increase the fraction of hypoxic tumor cells and, as a result, induce radiation resistance. Accordingly, future clinical trials with this class of agents must keep this in mind and be closely monitored.


The use of traditional cytotoxic chemotherapy drugs to augment the effectiveness of external beam radiation therapy in the treatment of solid tumors is established and well documented in the medical literature. The remarkable success of radiolabeled antibodies and radiolabeled peptides as systemic therapy for hematologie malignancies and neuroendocrine malignancies begs for even further improvement by evaluating the approaches reviewed in this article. Virtually no malignancies have been cured using single modalities of treatment. Therefore, studies are needed to explore combinations of systemically administered radiotherapy with one or a combination of the molecular targeted therapies. Combining drugs that have unique mechanisms of action and absence of overlapping toxicities with systemically administered radiotherapy should be exploited in future clinical trials. For example, once individual drug toxicities in combination with radiation have been established in humans, it would be interesting to explore various combinations such as cisplatin, EGF inhibitors, and antiangiogenic agents. This is an exciting time in clinical oncology research, because we have a plethora of new molecules to evaluate.


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26. Freyer G, Bossard N, Romestaing P, ct al. Addition of oxnliplatin to continuous fluorouracil, I-foIinic acid, and concomitant radiotherapy in rectal cancer: the Lyon R 97-03 phase I trial. J Clin Oncol. 2001; 19:2433-2438.

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Larry K. Kvols, MD,
H. Lee Moffitt Cancer Center and Research Institute, University of South Florida

January, 2005|Archive|

The Level of Evidence for Permitting a Qualified Health Claim: FDA’s Review of the Evidence for Selenium and Cancer and Vitamin E and Heart Disease1

  • 1/26/2005
  • Paula R. Trumbo
  • The American Society for Nutritional Sciences J. Nutr. 135:354-356, February 2005

Health claims are authorized for the labeling of foods when there is significant scientific agreement among qualified experts on the evidence for a relationship between a food or food component (substance) and a disease. Qualified health claims are permitted when there is less scientific evidence for a substance-disease relationship, therefore requiring qualifying language.

The evidence for a relationship between vitamin E and heart disease and selenium and cancer was reviewed by the U.S. FDA. It was determined that there was insufficient evidence to permit a qualified health claim for vitamin E and cancer, whereas there was some evidence for permitting a qualified health claim for selenium and cancer.

Author’s affiliation:
Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD 20740

January, 2005|Archive|

The predictive value of p53, p53R2, and p21 for the effect of chemoradiation therapy on oesophageal squamous cell carcinoma

  • 1/26/2005
  • H Okumura et al.
  • British Journal of Cancer (2005) 92, 284-289.

The p53 family regulates cell-cycle arrest, triggers apoptosis or is involved in repair of DNA damage. In the present study, we analysed the expression of some p53 family proteins and their responses to chemoradiation therapy (CRT) in cases of oesophageal squamous cell carcinoma (ESCC).

We immunohistochemically investigated the relationship between p53, p53R2, and p21 expression in biopsy specimens of untreated primary tumours and their clinical and histological responses to CRT in 62 patients with ESCC. Chemoradiation therapy consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation.

The rates of clinical and histological responses (complete or partial) to CRT were 71.0% (clinical) and 52.8% (histological). The rate of positive expression was 43.5% for p53, 37.1% for p53R2, and 54.8% for p21 expression. Statistically significant correlations were found between p53 or p53R2 expression and favourable response to CRT (P=0.0001 or 0.041 clinical, P=0.016 or 0.0018 histological, respectively).

Furthermore, in p53-negative tumours, CRT was more effective in tumours with p53R2 negative expression than those with p53R2 positive expression (P=0.0014). We demonstrated that the negative expression of p53 and p53R2 expression was closely related to the effect of CRT and should predict the CRT outcome in patients with ESCC.

H Okumura1, S Natsugoe1, M Matsumoto1, Y Mataki1, H Takatori1, S Ishigami1, S Takao1 and T Aikou1

Authors’ Affiliations:
1Department of Surgical Oncology, Digestive Surgery, Graduate School of Medicine, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima 890-8520, Japan

January, 2005|Archive|

Current Evidence and Research Needs to Support a Health Claim for Selenium and Cancer Prevention

  • 1/26/2005
  • Gerald F. Combs, Jr
  • The American Society for Nutritional Sciences J. Nutr. 135:343-347, February 2005

Selenium was recognized as a nutritional essential only in the late 1950s. That it might also be anticarcinogenic was first suggested a decade later based on ecological relationships of cancer mortality rates and forage crop Se contents in the United States.

Since that time, a substantial body of scientific evidence indicated that Se can, indeed, play a role in cancer prevention. This is supported by a remarkably consistent body of findings from studies with animal tumor and cell culture models, and by some, but not all epidemiologic observations. The body of clinical trial data is less extensive, yet also supportive. The consistent findings from this evidence are that both inorganic and organic Se-compounds can be antitumorigenic at doses greater than those required to support the maximal expression of the selenoenzymes that are generally regarded as discharging the nutritional effects of the element.

Although the plausibility of Se as a cancer-protective factor is clear, other research is required to support evidence-based evaluation of this hypothesis. In addition to further, well-planned clinical trials, that research must include the development of analytical tools for speciating Se in foods and biological tissues; the development of better means of assessing Se status in ways that are relevant to cancer prevention; and the determination of the minimal dose of Se that is both safe and effective in reducing cancer risk.

January, 2005|Archive|