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Pesticide Residues in Food and Cancer Risk: A Critical Analysis


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Public policy with respect to pesticides has relied on the results of high-dose, rodent cancer tests as the major source of information for assessing potential cancer risks to humans. This chapter critically examines the assumptions, methodology, results, and implications of cancer risk assessments of pesticide residues in the diet. The analyses presented in the chapter are based on results in the Carcinogenic Potency Database (CPDB), which provide the necessary data to examine the published literature of chronic animal cancer tests; the CPDB includes results of 5620 experiments on 1372 chemicals. A comparison of human exposure to synthetic pesticide residues in the diet to the broader and greater exposure to natural chemicals in the diet indicates an imbalance in both data and perception about possible carcinogenic hazards to humans from chemical exposures. The chapter examines the cancer risk assessment methodology, including the use of animal data from high-dose bioassays, in which half the chemicals tested are carcinogenic. Rankings of pesticides on the human exposure/rodent potency (HERP) index provides a broad perspective on possible cancer hazards from a variety of exposures to rodent carcinogens, including pesticide residues. An analysis of possible reasons for the wide disparities in published risk estimates for pesticide residues in the diet is presented in the chapter.
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Pesticide Residues in Food
and Cancer Risk:
A Critical Analysis
Lois Swirsky Gold, Thomas H. Slone, Bruce N. Ames
University of California, Berkeley
Neela B. Manley
Ernest Orlando Lawrence Berkeley National Laboratory
Possible cancer hazards from pesticide residues in food have
been much discussed and hotly debated in the scientific lit-
erature, the popular press, the political arena, and the courts.
Consumer opinion surveys indicate that much of the U.S. pub-
lic believes that pesticide residues in food are a serious cancer
hazard (Opinion Research Corporation, 1990). In contrast, epi-
demiologic studies indicate that the major preventable risk
factors for cancer are smoking, dietary imbalances, endogenous
hormones, and inflammation (e.g., from chronic infections).
Other important factors include intense sun exposure, lack of
physical activity, and excess alcohol consumption (Ames et al.,
1995). The types of cancer deaths that have decreased since
1950 are primarily stomach, cervical, uterine, and colorectal.
Overall cancer death rates in the United States (excluding lung
cancer) have declined 19% since 1950 (Ries et al., 2000). The
types that have increased are primarily lung cancer [87% is due
to smoking, as are 31% of all cancer deaths in the United States
(American Cancer Society, 2000)], melanoma (probably due to
sunburns), and non-Hodgkin’s lymphoma. If lung cancer is in-
cluded, mortality rates have increased over time, but recently
have declined (Ries et al., 2000).
Thus, epidemiological studies do not support the idea that
synthetic pesticide residuesare important for human cancer. Al-
though some epidemiologicstudies find an association between
cancer and low levels of some industrial pollutants, the stud-
ies often have weak or inconsistent results, rely on ecological
correlations or indirect exposure assessments, use small sam-
ple sizes, and do not control for confounding factors such as
composition of the diet, which is a potentially important con-
founding factor. Outside the workplace, the levels of exposure
to synthetic pollutants or pesticide residues are low and rarely
seem toxicologically plausible as a causal factor when com-
pared to the wide variety of naturally occurring chemicals to
which all people are exposed (Ames et al., 1987, 1990a; Gold
et al., 1992). Whereas public perceptions tend to identifychem-
icals as being only synthetic and only synthetic chemicals as
being toxic, every natural chemical is also toxic at some dose,
and the vast proportion of chemicals to which humans are ex-
posed are naturally occurring (see Section 38.2).
There is, however, a paradox in the public concern about
possible cancer hazards from pesticide residues in food and the
lack of public understanding of the substantial evidence indi-
cating that high consumption of the foods that contain pesticide
residues—fruits and vegetables—has a protective effect against
many types of cancer. A review of about 200 epidemiological
studies reported a consistent association between low consump-
tion of fruits and vegetables and cancer incidence at many target
sites (Block et al., 1992; Hill et al., 1994; Steinmetz and Potter,
1991). The quarter of the population with the lowest dietary
intake of fruits and vegetables has roughly twice the cancer
rate for many types of cancer (lung, larynx, oral cavity, esopha-
gus, stomach, colon and rectum, bladder, pancreas, cervix, and
ovary) compared to the quarter with the highest consumption
of those foods. The protective effect of consuming fruits and
vegetables is weaker and less consistent for hormonally related
cancers, such as breast and prostate. Studies suggest that in-
adequate intake of many micronutrients in these foods may be
radiation mimics and are important in the carcinogenic effect
(Ames, 2001). Despite the substantial evidence of the impor-
tance of fruits and vegetables in prevention, half the American
Handbook of Pesticide Toxicology Copyright © 2001 by Academic Press.
Volume 1. Principles All rights of reproduction in any form reserved.
Gold, L.S., Slone, T.H., Ames, B.N., and Manley, N.B. 
Pesticide Residues in Food and Cancer Risk: A Critical 
Analysis. In: Handbook of Pesticide Toxicology, Second 
Edition (R. Krieger, ed.), San Diego, CA: Academic 
Press, pp. 799-843 (2001).
800 CHAPTER 38 Pesticide Residues in Food and Cancer Risk: A Critical Analysis
public did not identify fruit and vegetable consumption as a
protective factor against cancer (U.S. National Cancer Institute,
1996). Consumption surveys, moreover, indicate that 80% of
children and adolescents in the United States (Krebs-Smith et
al., 1996) and 68% of adults (Krebs-Smith et al., 1995) did not
consume the intake of fruits and vegetables recommended by
the National Cancer Institute (NCI) and the National Research
Council: five servings per day. One important consequence of
inadequate consumption of fruits and vegetables is low intake
of some micronutrients. For example, folic acid is one of the
most common vitamin deficiencies in people who consume few
dietary fruits and vegetables; folate deficiency causes chromo-
some breaks in humans by a mechanism that mimics radiation
(Ames, 2001; Blount et al., 1997). Approximately 10% of the
U.S. population (Senti and Pilch, 1985) had a lower folate level
than that at which chromosome breaks occur (Blount et al.,
1997). Folate supplementation above the recommended daily
allowance (RDA) minimized chromosome breakage (Fenech et
al., 1998).
Given the lack of epidemiological evidence to link dietary
synthetic pesticide residues to human cancer, and taking into
account public concerns about pesticide residues as possible
cancer hazards, public policy with respect to pesticides has
relied on the results of high-dose, rodent cancer tests as the ma-
jor source of information for assessing potential cancer risks
to humans. This chapter examines critically the assumptions,
methodology, results, and implications of cancer risk assess-
ments of pesticide residues in the diet. Our analyses are based
on results in our Carcinogenic Potency Database (CPDB) (Gold
et al., 1997b, 1999;, which pro-
vide the necessary data to examine the published literature of
chronic animal cancer tests; the CPDB includes results of 5620
experiments on 1372 chemicals. Specifically, the following are
addressed in the section indicated:
Section 38.2. Human exposure to synthetic pesticide residues
it the diet compared to the broader and greater exposure to
natural chemicals in the diet
Section 38.3. Cancer risk assessment methodology, including
the use of animal data from high-dose bioassays in which
half the chemicals tested are carcinogenic
Section 38.4. Increased cell division as an important
hypothesis for the high positivity rate in rodent bioassays
and implications for risk assessment
Section 38.5. Providing a broad perspective on possible
cancer hazards from a variety of exposures to rodent
carcinogens, including pesticide residues, by ranking on the
HERP (human exposure/rodent potency) index
Section 38.6. Analysis of possible reasons for the wide
disparities in published risk estimates for pesticide residues
in the diet
Section 38.7. Identification and ranking of exposures in the
U.S. diet to naturally occurring chemicals that have not
been tested for carcinogenicity, using an index that takes
into account the acutely toxic dose of a chemical (LD50)
and average consumption in the U.S. diet
Section 38.8. Summary of carcinogenicity results on 193
active ingredients in commercial pesticides.
Current regulatory policy to reduce human cancer risks is based
on the idea that chemicals that induce tumors in rodent cancer
bioassays are potential human carcinogens. The chemicals se-
lected for testing in rodents, however, are primarily synthetic
(Gold et al., 1997a, b, c, 1998, 1999). The enormous back-
ground of human exposures to natural chemicals has not been
systematically examined. This has led to an imbalance in both
data and perception about possible carcinogenic hazards to hu-
mans from chemical exposures. The regulatoryprocess does not
take into account (1) that natural chemicals make up the vast
bulk of chemicals to which humans are exposed; (2) that the
toxicology of synthetic and natural toxins is not fundamentally
different; (3) that about half of the chemicals tested, whether
natural or synthetic, are carcinogens when tested using current
experimental protocols; (4) that testing for carcinogenicity at
near-toxic doses in rodents does not provide enough informa-
tion to predict the excess number of human cancers that might
occur at low-dose exposures; and (5) that testing at the max-
imum tolerated dose (MTD) frequently can cause chronic cell
killing and consequent cell replacement (a risk factor for cancer
that can be limited to high doses) and that ignoring this effect
in risk assessment can greatly exaggerate risks.
We estimate that about 99.9% of the chemicals that humans
ingest are naturally occurring. The amounts of synthetic pesti-
cide residues in plantfoods are low in comparison to the amount
of natural pesticides produced by plants themselves (Ames et
al., 1990a, b; Gold et al., 1997a). Of all dietary pesticides that
Americans eat, 99.99% are natural: They are the chemicals pro-
duced by plants to defend themselves against fungi,insects, and
other animal predators. Each plant produces a different array of
such chemicals (Ames et al., 1990a, b).
We estimate that the daily average U.S. exposure to natural
pesticides in the diet is about 1500 mg and to burnt mate-
rial from cooking is about 2000 mg (Ames et al., 1990b).
In comparison, the total daily exposure to all synthetic pesti-
cide residues combined is about 0.09 mg based on the sum
of residues reported by the U.S. Food and Drug Administra-
tion (FDA) in its study of the 200 synthetic pesticide residues
thought to be of greatest concern (Gunderson, 1988; U.S.
Food and Drug Administration, 1993a). Humans ingest roughly
5000–10,000 different natural pesticides and their breakdown
products (Ames et al., 1990a). Despite this enormously greater
exposure to natural chemicals, among the chemicals tested in
long-term bioassays in the CPDB, 77% (1050/1372) are syn-
thetic (i.e., do not occur naturally) (Gold and Zeiger, 1997; Gold
et al., 1999).
Concentrations of natural pesticides in plants are usually
found at parts per thousand or million rather than parts per
billion, which is the usual concentration of synthetic pesticide
38.2 Human Exposures to Natural and Synthetic Chemicals 801
Table 38.1
Carcinogenicity Status of Natural Pesticides Tested in Rodentsa
Acetaldehyde methylformylhydrazone, allyl isothiocyanate, arecoline·HCl, benzaldehyde, benzyl acetate, caffeic acid, capsaicin, cat-
echol, clivorine, coumarin, crotonaldehyde, 3,4-dihydrocoumarin, estragole, ethyl acrylate, N2-γ-glutamyl-p-hydrazinobenzoic acid,
hexanal methylformylhydrazine, p-hydrazinobenzoic acid·HCl, hydroquinone, 1-hydroxyanthraquinone, lasiocarpine, d-limonene,
3-methoxycatechol, 8-methoxypsoralen, N-methyl-N-formylhydrazine, α-methylbenzyl alcohol, 3-methylbutanal methylformylhy-
drazone, 4-methylcatechol, methylhydrazine, monocrotaline, pentanal methylformylhydrazone, petasitenine, quercetin, reserpine,
safrole, senkirkine, sesamol, symphytine
Atropine, benzyl alcohol, benzyl isothiocyanate, benzyl thiocyanate, biphenyl, d-carvone, codeine, deserpidine, disodium gly-
cyrrhizinate, ephedrine sulfate, epigallocatechin, eucalyptol, eugenol, gallic acid, geranyl acetate, β-N-[γ-l(+)-glutamyl]-4-
hydroxymethylphenylhydrazine, glycyrrhetinic acid, p-hydrazinobenzoic acid, isosafrole, kaempferol, dl-menthol, nicotine, norhar-
man, phenethyl isothiocyanate, pilocarpine, piperidine, protocatechuic acid, rotenone, rutin sulfate, sodium benzoate, tannic acid,
1-trans-δ9-tetrahydrocannabinol, turmeric oleoresin, vinblastine
aFungal toxins are not included.
bThese rodent carcinogens occur in absinthe, allspice, anise, apple, apricot, banana, basil, beet, black pepper, broccoli, Brussels sprouts, cabbage, cantaloupe,
caraway, cardamom, carrot, cauliflower, celery, cherries, chili pepper, chocolate, cinnamon, cloves, coffee, collard greens, comfrey herb tea, coriander, corn,
currants, dill, eggplant, endive, fennel, garlic, grapefruit, grapes, guava, honey, honeydew melon, horseradish, kale, lemon, lentils, lettuce, licorice, lime, mace,
mango, marjoram, mint, mushrooms, mustard, nutmeg, onion, orange, paprika, parsley, parsnip, peach, pear, peas, pineapple, plum, potato, radish, raspberries,
rhubarb, rosemary, rutabaga, sage, savory, sesame seeds, soybean, star anise, tarragon, tea, thyme, tomato, turmeric, and turnip.
residues. Therefore, because humans are exposed to so many
more natural than synthetic chemicals (by weight and by num-
ber), human exposure to natural rodent carcinogens, as defined
by high-dose rodent tests, is ubiquitous (Ames et al., 1990b). It
is probable that almost every fruit and vegetable in the super-
market contains natural pesticides that are rodent carcinogens.
Even though only a tiny proportion of natural pesticides have
been tested for carcinogenicity, 37 of 71 that have been tested
are rodent carcinogens that are present in the common foods
listed in Table 38.1.
Humans also ingest numerous natural chemicals that are pro-
duced as by-products of cooking food. For example, more than
1000 chemicals have been identified in roasted coffee, many of
which are produced by roasting (Clarke and Macrae, 1988; Ni-
jssen et al., 1996). Only 30 have been tested for carcinogenicity
according to the most recent results in our CPDB, and 21 of
these are positive in at least one test (Table 38.2), totaling at
least 10 mg of rodent carcinogens per cup of coffee (Clarke and
Macrae, 1988; Fujita et al., 1985; Kikugawa et al., 1989; Ni-
jssen et al., 1996). Among the rodent carcinogens in coffee are
the plant pesticides caffeic acid (present at 1800 ppm; Clarke
and Macrae, 1988) and catechol (present at 100 ppm; Rahn and
König, 1978; Tressl et al., 1978). Two other plant pesticides
in coffee, chlorogenic acid and neochlorogenic acid (present
at 21,600 and 11,600 ppm, respectively; Clarke and Macrae,
1988) are metabolized to caffeic acid and catechol but have not
been tested for carcinogenicity. Chlorogenic acid and caffeic
acid are mutagenic (Ariza et al., 1988; Fung et al., 1988; Han-
ham et al., 1983) and clastogenic (Ishidate et al., 1988; Stich
et al., 1981). Another plant pesticide in coffee, d-limonene, is
carcinogenic but the only tumors induced were in male rat kid-
ney, by a mechanism involving accumulation of α2u-globulin
and increased cell division in the kidney, which would not be
predictive of a carcinogenic hazard to humans (Dietrich and
Swenberg, 1991; Rice et al., 1999). Some other rodent carcino-
gens in coffee are products of cooking, for example, furfural
and benzo(a)pyrene. The point here is not to indicate that ro-
dent data necessarily implicate coffeeas a risk factor for human
cancer, but rather to illustrate that there is an enormous back-
ground of chemicals in the diet that are natural and that have not
been a focus of carcinogenicity testing. A diet free of naturally
occurring chemicals that are carcinogens in high-dose rodent
tests is impossible.
It is often assumed that because natural chemicals are part
of human evolutionary history, whereas synthetic chemicals are
recent, the mechanisms that have evolved in animals to cope
Table 38.2
Carcinogenicity Status of Natural Chemicals in Roasted Coffee
Acetaldehyde, benzaldehyde, benzene, benzofuran, benzo(a)pyrene, caffeic acid, catechol, 1,2,5,6-dibenzanthracene, ethanol, ethyl-
benzene, formaldehyde, furan, furfural, hydrogen peroxide, hydroquinone, isoprene, limonene, 4-methylcatechol, styrene, toluene,
Not positive:
Acrolein, biphenyl, choline, eugenol, nicotinamide, nicotinic acid, phenol, piperidine
Uncertain: Caffeine
Yet to test: 1000 chemicals
802 CHAPTER 38 Pesticide Residues in Food and Cancer Risk: A Critical Analysis
with the toxicity of natural chemicals will fail to protect against
synthetic chemicals, including synthetic pesticides (Ames et al.,
1987). This assumption is flawed for several reasons (Ames et
al., 1990b, 1996; Gold et al., 1997a, b, c):
1. Humans have many natural defenses that buffer against
normal exposures to toxins (Ames et al., 1990b) and these are
usually general, rather than tailored for each specific chemical.
Thus, they work against both natural and synthetic chemicals.
Examples of general defenses 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; deoxyribonucleic acid (DNA) repair
enzymes, which repair DNA that was damaged from many
different sources; and detoxification enzymes of the liver and
other organs, which generally target classes of chemicals
rather than individual chemicals. That human defenses are
usually general, rather than specific for each chemical, makes
good evolutionary sense. The reason that predators of plants
evolved general defenses is presumably to be prepared to
counter a diverse and ever-changing array of plant toxins in an
evolving world; if a herbivore had defenses against only a
specific set of toxins, it would be at great disadvantage in
obtaining new food when favored foods became scarce or
evolved new chemical defenses.
2. Various natural toxins, which have been present
throughout vertebrate evolutionary history, nevertheless cause
cancer in vertebrates (Ames et al., 1990b; Gold et al., 1997b,
1999; Vainio et al., 1995). Mold toxins, such as aflatoxin, have
been shown to cause cancer in rodents, monkeys, humans, and
other species. Many of the common elements, despite their
presence throughout evolution, are carcinogenic to humans at
high doses (e.g., the salts of cadmium, beryllium, nickel,
chromium, and arsenic). Furthermore, epidemiological studies
from various parts of the world indicate that certain natural
chemicals in food may be carcinogenic risks to humans; for
example, the chewing of betel nut with tobacco is associated
with oral cancer. Among the agents identified as human
carcinogens by the International Agency for Research in
Cancer (IARC) 62% (37/60) occur naturally: 16 are natural
chemicals, 11 are mixtures of natural chemicals, and 10 are
infectious agents (IARC, 1971–1999; Vainio et al., 1995).
Thus, the idea that a chemical is “safe” because it is natural, is
not correct.
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 last few thousand years. Indeed, very few of
the plants that humans eat today (e.g., coffee, cocoa, tea,
potatoes, tomatoes, corn, avocados, mangos, 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. Some early synthetic pesticides were lipophilic
organochlorines that persist in nature and bioaccumulate in
adipose tissue, for example, dichlorophenyltrichloroethane
(DDT), aldrin, and dieldrin (DDT is discussed in
Section 38.5). This ability to bioaccumulate is often seen as a
hazardous property of synthetic pesticides; however, such
bioconcentration and persistence are properties of relatively
few synthetic pesticides. Moreover, many thousands of
chlorinated chemicals are produced in nature (Gribble, 1996).
Natural pesticides also can bioconcentrate if they are fat
soluble. Potatoes, for example, were introduced into the
worldwide food supply a few hundred years ago; potatoes
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 glycoalkaloids
have been shown to cause reproductive abnormalities in
rodents (Ames et al., 1990b; Morris and Lee, 1984).
5. Because no plot of land is free from attack by insects,
plants need chemical defenses—either natural or synthetic—to
survive pest attack. Thus, there is a trade-off between
naturally-occurring pesticides and synthetic pesticides. One
consequence of efforts to reduce pesticide use is that some
plant breeders develop plants to be more insect resistant by
making them higher in natural pesticides. A recent case
illustrates the potential hazards of this approach to pest
control: When a major grower introduced a new variety of
highly insect-resistant celery into commerce, people who
handled the celery developed rashes when they were
subsequently exposed to sunlight. Some detective work found
that the pest-resistant celery contained 6200 parts per billion
(ppb) of carcinogenic (and mutagenic) psoralens instead of the
800 ppb present in common celery (Beier and Nigg, 1994;
Berkley et al., 1986; Seligman et al., 1987).
Because the toxicology of natural and synthetic chemicals is
similar, one expects, and finds, a similar positivity rate for car-
cinogenicity among synthetic and natural chemicals that have
been tested in rodent bioassays. Amongchemicals tested in rats
and mice in the CPDB, about half the natural chemicals are
positive, and about half of all chemicals tested are positive. This
high positivity rate in rodent carcinogenesis bioassays is consis-
tent for many data sets (Table 38.3): Among chemicals tested
in rats and mice, 59% (350/590) are positive in at least one
experiment, 60% of synthetic chemicals (271/451), and 57%
of naturally occurring chemicals (79/139). Among chemicals
tested in at least one species, 52% of natural pesticides (37/71)
are positive, 61% of fungaltoxins (14/23), and 70% of the natu-
rally occurring chemicals in roasted coffee (21/30) (Table38.2).
Among commercial pesticides reviewed by the EPA (U.S. Envi-
ronmental Protection Agency, 1998), the positivity rate is 41%
(79/193); this rate is similar among commercial pesticides that
also occur naturally and those that are only synthetic, as well
as between commercial pesticides that have been canceled and
those still in use. (See Section 38.8 for detailed summary results
38.3 The High Carcinogenicity Rate Among Chemicals Tested in Chronic Animal Cancer Tests 803
Table 38.3
Proportion of Chemicals Evaluated as Carcinogenic
Chemicals tested in both rats and micea
Chemicals in the CPDB 350/590 (59%)
Naturally occurring chemicals in the CPDB 79/139 (57%)
Synthetic chemicals in the CPDB 271/451 (60%)
Chemicals tested in rats and/or micea
Chemicals in the CPDB 702/1348 (52%)
Natural pesticides in the CPDB 37/71 (52%)
Mold toxins in the CPDB 14/23 (61%)
Chemicals in roasted coffee in the CPDB 21/30 (70%)
Commercial pesticides in the CPDB 79/193 (41%)
Physicians’ Desk Reference (PDR):
Drugs with reported cancer testsb117/241 (49%)
FDA database of drug submissionsc125/282 (44%)
aFrom the Carcinogenic Potency Database (Gold et al., 1997c, 1999).
bDavies and Monro (1995).
cContrera et al. (1997). 140 drugs are in both the FDA and the PDR databases.
of carcinogenicity tests on the 193 commercial pesticides in the
CPDB, including results on the positivity of each chemical, its
carcinogenic potency, and target organs of carcinogenesis.)
Because the results of high-dose rodent tests are routinely
used to identify a chemical as a possible cancer hazard to hu-
mans, it is important to try to understand how representative
the 50% positivity rate might be of all untested chemicals. If
half of all chemicals (both natural and synthetic) to which hu-
mans are exposed were positive if tested, then the utility of a
test to identify a chemical as a “potential human carcinogen”
because it increases tumor incidence in a rodent bioassay would
be questionable. To determine the true proportion of rodentcar-
cinogens among chemicals would require a comparison of a
random group of synthetic chemicals to a random group of nat-
ural chemicals. Such an analysis has not been done.
It has been argued that the high positivity rate is due to se-
lecting more suspicious chemicals to test for carcinogenicity.
For example, chemicals may be selected that are structurally
similar to known carcinogens or genotoxins. That is a likely
bias because cancer testing is both expensive and time con-
suming, making it prudent to test suspicious compounds. On
the other hand, chemicals are selected for testing for many
reasons, including the extent of human exposure, level of pro-
duction, and scientific questions about carcinogenesis. Among
chemicals tested in both rats and mice, chemicals that are muta-
genic in Salmonella are carcinogenic in rodent bioassays more
frequently than nonmutagens: 80% of mutagens are positive
(176/219) compared to 50% (135/271) of nonmutagens. Thus,
if testing is based on suspicion of carcinogenicity, then more
mutagens should be selected than nonmutagens; however, of
the chemicals tested in both species, 55% (271/490) are not
mutagenic. This suggests that prediction of positivity is often
not the basis for selecting a chemical to test. Another argument
against selection bias is the high positivity rate for drugs (Ta-
ble 38.3), because drug development tends to favor chemicals
that are not mutagens or suspected carcinogens. In the Physi-
cians’ Desk Reference (PDR), however, 49% (117/241) of the
drugs that report results of animal cancer tests are carcinogenic
(Davies and Monro, 1995) (Table 38.3).
Moreover, while some chemical classes are more often
carcinogenic in rodent bioassays than others (e.g., nitroso com-
pounds, aromatic amines, nitroaromatics, and chlorinated com-
pounds), prediction is still imperfect. For example, a prospec-
tive prediction exercise was conducted by several experts in
1990 in advance of the 2-year National Toxicology Program
bioassays. There was wide disagreement among the experts on
which chemicals would be carcinogenic when tested, and the
level of accuracy varied by expert, thus indicating that predic-
tive knowledge is uncertain (Omenn et al., 1995).
One large series of mouse experiments by Innes et al. (1969)
has frequently been cited (U.S. National Cancer Institute, 1984)
as evidence that the true proportion of rodent carcinogens is ac-
tually low among tested substances (Table 38.4). In the Innes
study, 119 synthetic pesticides and industrial chemicals were
tested, and only 11 (9%) were evaluated as carcinogenic. Our
analysis indicates that those early experiments lacked power to
detect an effect because they were conducted only in mice (not
in rats), they included only 18 animals in a group (compared
with the standard protocol of 50), the animals were tested for
only 18 months (compared with the standard 24 months), and
the Innes dose was usuallylower than the highest dose in subse-
quent mouse tests if the same chemical was tested again (Gold
and Zeiger, 1997; Gold et al., 1999; Innes et al., 1969).
To assess whether the low positivity rate in the Innes study
was due to the lack of power in the design of the experiments,
we used results in our CPDB to examine subsequent bioassays
on the Innes chemicals that had not been evaluated as positive
(results and chemical names are reported in Table 38.4). Among
the 34 chemicals that were not positive in the Innes study and
were subsequently retested with more standard protocols, 17
had a subsequent positive evaluation of carcinogenicity (50%),
which is similar to the proportion among all chemicals in the
CPDB (Table 38.4). Of the 17 new positives, 7 were carcino-
genic in mice and 14 in rats. Innes et al. had recommended
further evaluation of some chemicals that had inconclusive re-
sults in their study. If those were the chemicals subsequently
retested, then one might argue that they would be the most
likely to be positive. Our analysis does not support that view,
however. We found that the positivity rate among the chemicals
that the Innes study said needed further evaluation was 7 of 16
(44%) when retested, compared to 10 of 18 (56%) among the
chemicals that Innes evaluated as negative. Our analysis thus
supports the idea that the low positivity rate in the Innes study
resulted from lack of power.
Because many of the chemicals tested by Innes et al. were
synthetic pesticides, we reexamined the question of what pro-
portion of synthetic pesticides are carcinogenic (as shown in
Table 38.3) by excluding the pesticides tested only in the Innes
series. The Innes studies had little effect on the positivity rate:
Table 38.3 indicates that of all commercial pesticides in the
804 CHAPTER 38 Pesticide Residues in Food and Cancer Risk: A Critical Analysis
Table 38.4
Results of Subsequent Tests on Chemicals (Primarily Pesticides) not Found Carcinogenic by Innes et al. (1969)
Percentage carcinogenic when retested
Retested chemicals Mice Rats Either mice or rats
All retested 7/26 (27%) 14/34 (41%) 17/34 (50%)
Innes: not carcinogenic 3/10 (30%) 9/18 (50%) 10/18 (56%)
Innes: needs further evaluation 4/16 (25%) 5/16 (31%) 7/16 (44%)
Of 119 chemicals tested by Innes et al., 11 (9%) were evaluated as positive by Innes et al.
Carcinogenic when retested: atrazine (R), azobenzene(R), captan (M, R), carbaryl (R), 3-(p-chlorophenyl)-1,1-dimethylurea(R), p,p-DDD(M), folpet (M),
manganese ethylenebisthiocarbamate (R), 2-mercaptobenzothiazole (R), N-nitrosodiphenylamine(R), 2,3,4,5,6-pentachlorophenol (M, R), o-phenylphenol (R),
piperonyl butoxide(M, R), piperonyl sulfoxide(M), 2,4,6-trichlorophenol(M, R), zinc dimethyldithiocarbamate (R), zinc ethylenebisthiocarbamate (R).
Not carcinogenic when retested: (2-chloroethyl)trimethylammonium chloride, calcium cyanamide, diphenyl-p-phenylenediamine, endosulfan, p,p-
ethyl-DDD, ethyl tellurac, isopropyl-N-(3-chlorophenyl) carbamate, lead dimethyldithiocarbamate, maleic hydrazide, mexacarbate, monochloroacetic
acid, phenyl-β-naphthylamine, rotenone, sodium diethyldithiocarbamate trihydrate, tetraethylthiuram disulfide, tetramethylthiuram disulfide, 2,4,5-
trichlorophenoxyacetic acid.
(M), positive in mice when retested; (R), positive in rats when retested; , Innes et al. stated that further testing was needed.
CPDB, 41% 79/193 are rodent carcinogens; when the analy-
sis is repeated by excludingthose Innes tests, 47% (77/165) are
What might explain the high proportion of chemicals that
are carcinogenic when tested in rodent cancer bioassays (Ta-
ble 38.3)? In standard cancer tests, rodents are given a chronic,
near-toxic dose: the maximum tolerated dose (MTD). Evidence
is accumulating that cell division caused by the high dose it-
self, rather than the chemical per se, contributes to cancer in
such tests (Ames and Gold, 1990; Ames et al., 1993a; But-
terworth and Bogdanffy, 1999; Cohen, 1998; Cunningham,
1996; Cunningham and Matthews, 1991; Cunningham et al.,
1991; Heddle, 1998). High doses can cause chronic wounding
of tissues, cell death, and consequent chronic cell division of
neighboring cells, which is a risk factor for cancer (Ames and
Gold, 1990; Gold et al., 1998). Each time a cell divides, there is
some probability that a mutation will occur, and thus increased
cell division increases the risk of cancer. At the low levels of
pesticide residues to which humans are usually exposed, such
increased cell division does not occur. The process of mutage-
nesis and carcinogenesis is complicated because many factors
are involved, for example, DNA lesions, DNA repair, cell di-
vision, clonal instability, apoptosis, and p53 (a cell cycle gene
that is mutated in half of human tumors) (Christensen et al.,
1999; Hill et al., 1999). The normal endogenous level of oxida-
tive DNA lesions in somatic cells is appreciable (Helbock et al.,
1998). In addition, tissues injured by high doses of chemicals
have an inflammatory immune response involving activation of
white cells in response to cell death (Adachi et al., 1995; Czaja
et al., 1994; Gunawardhana et al., 1993; Laskin and Pendino,
1995; Roberts and Kimber, 1999). Activated white cells release
mutagenic oxidants (including peroxynitrite, hypochlorite, and
H2O2). Therefore, the very low levels of synthetic pesticide
residues to which humans are exposed may pose no or only
minimal cancer risks.
It seems likely that a high proportion of all chemicals,
whether synthetic or natural, might be “carcinogens” if admin-
istered in the standard rodent bioassay at the MTD, primarily
due to the effects of high doses on cell division and DNA dam-
age (Ames and Gold, 1990; Ames et al., 1993a; Butterworth
et al., 1995; Cunningham, 1996; Cunningham and Matthews,
1991; Cunningham et al., 1991). For nonmutagens, cell division
at the MTD can increase carcinogenicity; for mutagens, there
can be a synergistic effect between DNA damage and cell divi-
sion at high doses. Ad libitum feeding in the standard bioassay
can also contribute to the high positivity rate (Hart et al., 1995).
In calorie-restricted mice, cell division rates are markedly lower
in several tissues than in ad libitum–fed mice (Lok et al., 1990).
In dosed animals, food restriction decreased tumor incidence at
all three sites that were evaluated as target sites (pancreas and
bladder in male rats, liver in male mice), and none of those sites
was evaluated as target sites after 2 or 3 years (U.S. National
Toxicology Program, 1997). In standard National Cancer Insti-
tute (NCI)/National Toxicology Program (NTP) bioassays, for
both control and dosed animals, food restriction improves sur-
vival and at the same time decreases tumor incidence at many
sites compared to ad libitum–feeding.
Without additional data on how a chemical causes cancer,
the interpretation of a positive result in a rodent bioassay is
highly uncertain. Although cell division is not measured in rou-
tine cancer tests, many studies on rodent carcinogenicity show a
correlation between cell division at the MTD and cancer (Cun-
ningham et al., 1995; Gold et al., 1998; Hayward et al., 1995).
Extensive reviews of bioassay results document that chronic
cell division can induce cancer (Ames and Gold, 1990; Ames
et al., 1993b; Cohen, 1995b; Cohen and Ellwein, 1991; Cohen
and Lawson, 1995; Counts and Goodman, 1995; Gold et al.,
1997b). A large epidemiological literature reviewed by Preston-
Martin et al. (1990, 1995) indicates that increased cell division
by hormones and other agents can increase human cancer.
38.4 The Importance of Cell Division in Mutagenesis and Carcinogenesis 805
Several of our findings in large-scale analyses of the results
of animal cancer tests (Gold et al., 1993) are consistent with
the idea that cell division increases the carcinogenic effect in
high-dose bioassays, including the high proportion of chemicals
that are positive; the high proportion of rodent carcinogens that
are not mutagenic; and the fact that mutagens, which can both
damage DNA and increase cell division at high doses, are more
likely than nonmutagensto be positive, to inducetumors in both
rats and mice, and to induce tumors at multiple sites (Gold et
al., 1993, 1998). Analyses of the limited data on dose response
in bioassays are consistent with the idea that cell division from
cell killing and cell replacement is important. Among rodent
bioassays with two doses and a control group, about half the
sites evaluated as target sites are statistically significant at the
MTD but not at half the MTD (p<0.05). The proportions are
similar for mutagens (44%, 148/334) and nonmutagens (47%,
76/163) (Gold and Zeiger, 1997; Gold et al., 1999), suggesting
that cell division at the MTD may be important for the carcino-
genic response of mutagens as well as nonmutagens that are
rodent carcinogens.
To the extent that increases in tumor incidence in rodent
studies are due to the secondary effects of inducing cell division
at the MTD, then any chemical is a likely rodent carcinogen,
and carcinogenic effects can be limited to high doses. Linearity
of the dose–response relationship also seems less likely than has
been assumed because of the inducibility of numerous defense
enzymes that deal with exogenous chemicals as groups (e.g.,
oxidants, electrophiles) and thus protect humans against nat-
ural and synthetic chemicals, including potentially mutagenic
reactive chemicals (Ames et al., 1990b; Luckey, 1999; Munday
and Munday, 1999; Trosko, 1998). Thus, true risks at the low
doses of most exposures to the general population are likely
to be much lower than what would be predicted by the linear
model that has been the default in U.S. regulatory risk assess-
ment. The true risk might often be 0.
Agencies that evaluate potential cancer risks to humans
are moving to take mechanism and nonlinearity into account.
The U.S. Environmental Protection Agency (EPA) recently
proposed new cancer risk assessment guidelines (U.S. Envi-
ronmental Protection Agency, 1996a) that emphasize a more
flexible approach to risk assessment and call for the use of more
biological information in the weight-of-evidence evaluation of
carcinogenicity for a given chemical and in the dose–response
assessment. The proposed changes take into account the issues
that were discussed previously.The new EPA guidelines recog-
nize the dose dependence of many toxicokinetic and metabolic
processes and the importance of understanding cancer mecha-
nisms for a chemical. The guidelines use nonlinear approaches
to low-dose extrapolation if warranted by mechanistic data and
a possible threshold of dose below which effects will not occur
(National Research Council, 1994; U.S. Environmental Pro-
tection Agency, 1996a). In addition, toxicological results for
cancer and noncancer endpoints could be incorporated together
in the risk assessment process.
Also consistent with the results discussed previously, are
the recent IARC consensus criteria for evaluations of carcino-
genicity in rodent studies, which take into account that an
agent can cause cancer in laboratory animals through a mech-
anism that does not operate in humans (Rice et al., 1999).
The tumors in such cases involve persistent hyperplasia in
cell types from which the tumors arise. These include urinary
bladder carcinomas associated with certain urinary precipitates,
thyroid follicular-cell tumors associated with altered thyroid-
stimulating hormone (TSH), and cortical tumors of the kidney
that arise only in male rats in association with nephropathy that
is due to α2u urinary globulin.
Historically, in U.S. regulatory policy, the “virtually safe
dose, corresponding to a maximum, hypothetical risk of one
cancer in a million, has routinely been estimated from results of
carcinogenesis bioassays using a linear model, which assumes
that there are no unique effects of high doses. To the extent that
carcinogenicity in rodent bioassays is due to the effects of high
doses for the nonmutagens, and a synergistic effect of cell divi-
sion at high doses with DNA damage for the mutagens, this
model overestimates risk (Butterworth and Bogdanffy, 1999;
Gaylor and Gold, 1998).
We have discussed validity problems associated with the use
of the limited data from animal cancer tests for human risk as-
sessment (Bernstein et al., 1985; Gold et al., 1998). Standard
practice in regulatory risk assessment for a given rodent car-
cinogen has been to extrapolate from the high doses of rodent
bioassays to the low doses of most human exposures by mul-
tiplying carcinogenic potency in rodents by human exposure.
Strikingly, however, due to the relatively narrow range of doses
in 2-year rodent bioassays and the limited range of statistically
significant tumor incidence rates, the various measures of po-
tency obtained from 2-year bioassays, such as the EPA q
the TD50, and the lower confidence limit on the TD10 (LTD10),
are constrained to a relatively narrow range of values about the
MTD, in the absence of 100% tumor incidence at the target
site, which rarely occurs (Bernstein et al., 1985; Freedman et
al., 1993; Gaylor and Gold, 1995, 1998; Gold et al., 1997b).
For example, the dose usually estimated by regulatory agen-
cies to give one cancer in a million can be approximated simply
by using the MTD as a surrogate for carcinogenic potency.
The “virtually safe dose” (VSD) can be approximated from the
MTD. Gaylor and Gold (1995) used the ratio MTD/TD50 and
the relationship between q
1and TD50 found by Krewski et al.
(1993) to estimate the VSD. The VSD was approximated by
the MTD/740,000 for rodent carcinogens tested in the bioas-
say program of the NCI/NTP. The MTD/740,000 was within a
factor of 10 of the VSD for 96% of carcinogens. This is simi-
lar to the finding that in near-replicate experiments of the same
chemical, potency estimates vary by a factor of 4 around a me-
dian value (Gold et al., 1987a; Gold et al., 1989; Gaylor et al.,
Using the benchmark dose approach proposed in the EPA
carcinogen guidelines, risk estimation is similarly constrained
by bioassay design. A simple, quick, and relatively precise de-
termination of the LTD10 can be obtained by the MTD divided
by 7 (Gaylor and Gold, 1998). Both linear extrapolation and
the use of safety or uncertainty factors proportionately reduce
806 CHAPTER 38 Pesticide Residues in Food and Cancer Risk: A Critical Analysis
a tumor dose in a similar manner. The difference in the regu-
latory “safe dose,” if any, for the two approaches depends on
the magnitude of uncertainty factors selected. Using the bench-
mark dose approach of the proposed carcinogen risk assessment
guidelines, the dose estimated from the LTD10 divided, for ex-
ample, by a 1000-fold uncertainty factor, is similar to the dose
of an estimated risk of less than 104using a linear model.
This dose is 100 times higher than the VSD corresponding to
an estimated risk of less than 106. Thus, whether the proce-
dure involves a benchmark dose or a linearized model, cancer
risk estimation is constrained by the bioassay design.
Given the lack of epidemiological data to link pesticide residues
to human cancer, as well as the limitations of cancer bioassays
for estimating risks to humans at low exposure levels, the high
positivity rate in bioassays, and the ubiquitous human expo-
sures to naturally occurring chemicals in the normal diet that
are rodent carcinogens (Tables 38.1–38.3), how can bioassay
data best be used if our goal is to evaluate potential carcino-
genic hazards to humans from pesticide residues in the diet? In
several papers, we have emphasized the importance of setting
research and regulatory priorities by gaining a broad perspec-
tive about the vast number of chemicals to which humans are
exposed. A comparison of potential hazards can be helpful in
efforts to communicate to the public what might be important
factors in cancer prevention and when selecting chemicals for
chronic bioassay, mechanistic, or epidemiologic studies (Ames
et al., 1987, 1990b; Gold and Zeiger, 1997; Gold et al., 1992).
There is a need to identify what might be the important cancer
hazards among the ubiquitous exposures to rodent carcinogens
in everyday life.
One reasonable strategy for setting priorities is to use a
rough index to compare and rank possible carcinogenic hazards
from a wide variety of chemical exposures to rodent carcino-
gens at levels that humans receive, and then to focus on those
that rank highest in possible hazard (Ames et al., 1987; Gold
et al., 1992, 1994a). Ranking is thus a critical first step. Al-
though 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 the possible hazards at the
bottom of a ranking if, using the same methodology to iden-
tify a hazard, there are numerous common human exposures
with much greater possible hazards. Our analyses are based on
the HERP (human exposure/rodent potency) index, which indi-
cates what percentage of the rodent carcinogenic dose (TD50 in
mg/kg/day) a human receives from a given average daily expo-
sure for a lifetime (mg/kg/day). TD50 values in our CPDB span
a 10 million–fold range across chemicals (Gold et al., 1997c).
Human exposures to rodent carcinogens range enormously as
well, from historically high workplace exposures in some occu-
pations or pharmaceutical dosages to very low exposures from
residues of synthetic chemicals in food or water.
The rank order of possible hazards for the given exposure
estimates will be similar for the HERP ranking, for a rank-
ing of regulatory “risk estimates” based on a linear model, or
for a ranking based on TD10, since all 3 methods are pro-
portional to the dose. Overall, our analyses have shown that
synthetic pesticide residues rank low in possible carcinogenic
hazards compared to many common exposures. HERP values
for some historically high exposures in the workplace and some
pharmaceuticals rank high, and there is an enormous back-
ground of naturally occurring rodent carcinogens in typical
portions or average consumption of common foods. This result
casts doubt on the relative importance of low-dose exposures
to residues of synthetic chemicals such as pesticides (Ames et
al., 1987; Gold et al., 1992, 1994a). A committee of the Na-
tional Research Council recently reached similar conclusions
about natural versus synthetic chemicals in the diet and called
for further research on natural chemicals (National Research
Council, 1996). (See Section 38.7 for further work on natural
The HERP ranking in Table 38.5 is for average U.S. ex-
posures to all rodent carcinogens in the CPDB for which
concentration data and average exposure or consumption data
were both available, and for which known exposure could be
chronic for a lifetime. For pharmaceuticals the doses are rec-
ommended doses; for the workplace, they are past industry
or occupation averages. The 87 exposures in the ranking (Ta-
ble 38.5) are ordered by possible carcinogenic hazard (HERP),
and natural chemicals in the diet are reported in boldface. Our
early HERP rankings were for typical dietary exposures (Ames
et al., 1987; Gold et al., 1992), and results are similar.
Several HERP values make convenient reference points for
interpreting Table 38.5. The median HERP value is 0.0025%,
and the background HERP for the average chloroform level in
a liter of U.S. tap water is 0.0003%. A HERP of 0.00001% is
approximately equal to a regulatory VSD risk of 106based on
the linearized multi-stage model (Gold et al., 1992). Using the
benchmark dose approach recommended in the new EPA guide-
lines with the LTD10 as the point of departure (POD), linear
extrapolation would produce a similar estimate of risk at 106
and hence a similar HERP value (Gaylor and Gold, 1998), if
information on the carcinogenic mode of action for a chemical
supports a nonlinear dose–response curve. The EPA guidelines
call for a margin-of-exposure approach with the LTD10 as the
POD. Based on that approach, the reference dose using a safety
or uncertainty factor of 1000 (i.e., LD10/1000) would be equiv-
alent to a HERP value of 0.001%, which is similar to a risk of
104based on a linear model. If the dose–response relationship
is judged to be nonlinear, then the cancer risk estimate will de-
pend on the number and magnitude of safety factors used in the
The HERP ranking maximizes possible hazards to synthetic
chemicals because it includes historically high exposure val-
ues that are now much lower [e.g., DDT, saccharin, butylated
hydroxyanisole (BHA), and some occupational exposures]. Ad-
ditionally, the values for dietary pesticide residues are averages
in the total diet, whereas for most natural chemicals the ex-
38.5 The HERP Ranking of Possible Carcinogenic Hazards 807
Table 38.5
Ranking Possible Carcinogenic Hazards from Average U.S. Exposures to Rodent Carcinogens
hazard: Potency TD50
HERP Human dose of (mg/kg/day)a
(%) Average daily U.S. exposure rodent carcinogen Rats Mice Exposure references
140 EDB: production workers (high Ethylene dibromide, 150 mg 1.52 (7.45) Ott et al. (1980), Ramsey et al. (1978)
exposure) (before 1977)
17 Clofibrate Clofibrate, 2 g 169 ·Havel and Kane (1982)
14 Phenobarbital, 1 sleeping pill Phenobarbital, 60 mg (+) 6.09 AMA (1983)
6.8 1,3-Butadiene: rubber industry workers 1,3-Butadiene, 66.0 mg (261) 13.9 Matanoski et al. (1993)
6.2 Comfrey–pepsin tablets, 9 daily Comfrey root, 2.7 g 626 ·Hirono et al. (1978), Culvenor et al. (1980)
(no longer recommended)
6.1 Tetrachloroethylene: dry cleaners with Tetrachloroethylene, 433 mg 101 (126) Andrasik and Cloutet (1990)
dry-to-dry units (1980–1990)
4.0 Formaldehyde: production workers Formaldehyde, 6.1 mg 2.19 (43.9) Siegal et al. (1983)
2.4 Acrylonitrile: production workers Acrylonitrile, 405 µg 16.9 ·Blair et al. (1998)
2.2 Trichloroethylene: vapor degreasing Trichloroethylene, 1.02 g 668 (1580) Page and Arthur (1978)
(before 1977)
2.1 Beer, 257 g Ethyl alcohol, 13.1 ml 9110 (—) Stofberg and Grundschober (1987)
1.4 Mobile home air (14 h/day) Formaldehyde, 2.2 mg 2.19 (43.9) Connor et al. (1985)
1.3 Comfrey–pepsin tablets, 9 daily Symphytine, 1.8 mg 1.91 ·Hirono et al. (1978), Culvenor et al. (1980)
(no longer recommended)
0.9 Methylene chloride: workers, industry Methylene chloride, 471 mg 724 (1100) CONSAD (1990)
average (1940s–1980s)
0.5 Wine, 28.0 g Ethyl alcohol, 3.36 ml 9110 (—) Stofberg and Grundschober (1987)
0.5 Dehydroepiandrosterone (DHEA) DHEA supplement, 25 mg 68.1 ·
0.4 Conventional home air (14 h/day) Formaldehyde, 598 µg 2.19 (43.9) McCann et al. (1987)
0.2 Omeprazole Omeprazole, 20 mg 199 (—) PDR (1998)
0.2 Fluvastatin Fluvastatin, 20 mg 125 ·PDR (1998)
0.1 Coffee, 13.3 g Caffeic acid, 23.9 mg 297 (4900) Stofberg and Grundschober (1987),
Clarke and Macrae (1988)
0.1 d-Limonene in food d-Limonene, 15.5 mg 204 (—) Stofberg and Grundschober (1987)
0.04 Bread, 67.6 g Ethyl Alcohol 243 mg 9110 (—) Stofberg and Grundschober (1987),
Wolm et al. (1974)
0.04 Lettuce, 14.9 g Caffeic acid, 7.90 mg 297 (4900) TAS (1989), Herrmann (1978)
0.03 Safrole in spices Safrole, 1.2 mg (441) 51.3 Hall et al. (1989)
0.03 Orange juice, 138 g d-Limonene, 4.28 mg 204 (—) TAS (1989), Schreier et al. (1979)
0.03 Comfrey herb tea, 1 cup (1.5 g root) Symphytine, 38 µg1.91 ·Culvenor et al. (1980)
(no longer recommended)
0.03 Tomato, 88.7 g Caffeic acid, 5.46 mg 297 (4900) TAS (1989), Schmidtlein and Herrmann (1975a)
0.03 Pepper, black, 446 mg d-Limonene, 3.57 mg 204 (—) Stofberg and Grundschober (1987),
Hasselstrom et al. (1957)
0.02 Coffee, 13.3 g Catechol, 1.33 mg 88.8 (244) Stofberg and Grundschober (1987),
Tressl et al. (1978), Rahn and König (1978)
0.02 Furfural in food Furfural, 2.72 mg (683) 197 Stofberg and Grundschober (1987)
0.02 Mushroom (Agaricus bisporus) 2.55 g Mixture of hydrazines, etc. 20,300 Stofberg and Grundschober (1987),
(whole mushroom) Toth and Erickson (1986),
Matsumoto et al. (1991)
808 CHAPTER 38 Pesticide Residues in Food and Cancer Risk: A Critical Analysis
Table 38.5
hazard: Potency TD50
HERP Human dose of (mg/kg/day)a
(%) Average daily U.S. exposure rodent carcinogen Rats Mice Exposure references
0.02 Apple, 32.0 g Caffeic acid, 3.40 mg 297 (4900) EPA (1989a), Mosel and Herrmann (1974)
0.02 Coffee, 13.3 g Furfural, 2.09 mg (683) 197 Stofberg and Grundschober (1987)
0.01 BHA: daily U.S. avg (1975) BHA, 4.6 mg 606 (5530) FDA (1991b)
0.01 Beer (before 1979), 257 g Dimethylnitrosamine, 726 ng 0.0959 (0.189) Stofberg and Grundschober (1987),
Fazio et al. (1980),
Preussmann and Eisenbrand (1984)
0.008 Aflatoxin: daily U.S. avg (1984–1989) Aflatoxin, 18 ng 0.0032 (+) FDA (1992b)
0.007 Cinnamon, 21.9 mg Coumarin, 65.0 µg13.9 (103) Poole and Poole (1994)
0.006 Coffee, 13.3 g Hydroquinone, 333 µg82.8 (225) Stofberg and Grundschober (1987),
Tressl et al. (1978),
Heinrich and Baltes (1987)
0.005 Saccharin: daily U.S. avg (1977) Saccharin, 7 mg 2140 (—) NRC (1979)
0.005 Carrot, 12.1 g Aniline, 624 µg194b(—) TAS (1989), Neurath et al. (1977)
0.004 Potato, 54.9 g Caffeic acid, 867 µg297 (4900) TAS (1989), Schmidtlein and Herrmann
0.004 Celery, 7.95 g Caffeic acid, 858 µg297 (4900) ERS (1994), Stöhr and Herrmann (1975)
0.004 White bread, 67.6 g Furfural, 500 µg(683) 197 Stofberg and Grundschober (1987)
0.003 d-Limonene Food additive, 475 µg 204 (—) Clydesdale (1997)
0.003 Nutmeg, 27.4 mg d-Limonene, 466 µg204 (—) Stofberg and Grundschober (1987),
Bejnarowicz and Kirch (1963)
0.003 Conventional home air (14 h/day) Benzene, 155 µg (169) 77.5 McCann et al. (1987)
0.002 Coffee, 13.3 g 4-Methylcatechol, 433 µg248 ·Stofberg and Grundschober (1987),
Heinrich and Baltes (1987),
IARC (1991)
0.002 Carrot, 12.1 g Caffeic acid, 374 µg297 (4900) TAS (1989), Stöhr and Herrmann (1975)
0.002 Ethylene thiourea: daily U.S. avg (1990) Ethylene thiourea, 9.51 µg 7.9 (23.5) EPA (1991a)
0.002 BHA: daily U.S. avg (1987) BHA, 700 µg 606 (5530) FDA (1991b)
0.002 DDT: daily U.S. avg (before 1972 ban)dDDT, 13.8 µg (84.7) 12.8 Duggan and Corneliussen (1972)
0.001 Plum, 2.00 g Caffeic acid, 276 µg297 (4900) ERS (1995), Mosel and Herrmann (1974)
0.001 Pear, 3.29 g Caffeic acid, 240 µg297 (4900) Stofberg and Grundschober (1987),
Mosel and Herrmann (1974)
0.001 [UDMH: daily U.S. avg (1988)] [UDMH, 2.82 µg (from Alar)] (—) 3.96 EPA (1989a)
0.0009 Brown mustard, 68.4 mg Allyl isothiocyanate, 62.9 µg96 (—) Stofberg and Grundschober (1987),
Carlson et al. (1987)
0.0008 DDE: daily U.S. avg (before 1972 ban)dDDE, 6.91 µg (—) 12.5 Duggan and Corneliussen (1972)
0.0007 TCDD: daily U.S. avg (1994) TCDD, 12.0 pg 0.0000235 (0.000156) EPA (1994b)
0.0006 Bacon, 11.5 g Diethylnitrosamine, 11.5 ng 0.0266 (+) Stofberg and Grundschober (1987),
Sen et al. (1979)
0.0006 Mushroom (Agaricus bisporus) 2.55 g Glutamyl-p-hydrazinobenzoate, ·277 Stofberg and Grundschober (1987),
107 µgChauhan et al. (1985)
0.0005 Bacon, 11.5 g Dimethylnitrosamine, 34.5 ng 0.0959 (0.189) Stofberg and Grundschober (1987),
Sen et al. (1979)
0.0004 Bacon, 11.5 g N-Nitrosopyrrolidine, 196 ng (0.799) 0.679 Stofberg and Grundschober (1987),
Tricker and Preussmann (1991)
0.0004 EDB: daily U.S. avg (before 1984 ban)dEDB, 420 ng 1.52 (7.45) EPA (1984b)
0.0004 Tap water, 1 liter (1987–1992) Bromodichloromethane, 13 µg (72.5) 47.7 AWWA (1993)
0.0003 Mango, 1.22 g d-Limonene, 48.8 µg204 (—) ERS (1995), Engel and Tressl (1983)
38.5 The HERP Ranking of Possible Carcinogenic Hazards 809
Table 38.5
hazard: Potency TD50
HERP Human dose of (mg/kg/day)a
(%) Average daily U.S. exposure rodent carcinogen Rats Mice Exposure references
0.0003 Beer, 257 g Furfural, 39.9 µg(683) 197 Stofberg and Grundschober (1987)
0.0003 Tap water, 1 liter (1987–1992) Chloroform, 17 µg (262) 90.3 AWWA (1993)
0.0003 Beer (1994–1995), 257 g Dimethylnitrosamine, 18 ng 0.0959 (0.189) Glória et al. (1997)
0.0003 Carbaryl: daily U.S. avg (1990) Carbaryl, 2.6 µg 14.1 (—) FDA (1991a)
0.0002 Celery, 7.95 g 8-Methoxypsoralen, 4.86 µg32.4 (—) ERS (1994), Beier et al. (1983)
0.0002 Toxaphene: daily U.S. avg (1990)dToxaphene, 595 ng (—) 5.57 FDA (1991a)
0.00009 Mushroom (Agaricus bisporus), p-Hydrazinobenzoate, 28 µg·454bStofberg and Grundschober (1987),
2.55 g Chauhan et al. (1985)
0.00008 PCBs: daily U.S. avg (1984–1986) PCBs, 98 ng 1.74 (9.58) Gunderson (1995)
0.00008 DDE/DDT: daily U.S. avg (1990)dDDE, 659 ng (—) 12.5 FDA (1991a)
0.00007 Parsnip, 54.0 mg 8-Methoxypsoralen, 1.57 µg32.4 (—) UFFVA (1989), Ivie et al. (1981)
0.00007 Toast, 67.6 g Urethane, 811 ng (41.3) 16.9 Stofberg and Grundschober (1987),
Canas et al. (1989)
0.00006 Hamburger, pan fried, 85 g PhIP, 176 ng 4.22b(28.6b) TAS (1989), Knize et al. (1994)
0.00006 Furfural Food additive, 7.77 µg (683) 197 Clydesdale (1997)
0.00005 Estragole in spices Estragole, 1.99 µg·51.8 Stofberg and Grundschober (1987)
0.00005 Parsley, fresh, 324 mg 8-Methoxypsoralen, 1.17 µg32.4 (—) UFFVA (1989), Chaudhary et al. (1986)
0.00005 Estragole Food additive, 1.78 µg·51.8 Clydesdale (1997)
0.00003 Hamburger, pan fried, 85 g MeIQx, 38.1 ng 1.66 (24.3) TAS (1989), Knize et al. (1994)
0.00002 Dicofol: daily U.S. avg (1990) Dicofol, 544 ng (—) 32.9 FDA (1991a)
0.00001 Beer, 257 g Urethane, 115 ng (41.3) 16.9 Stofberg and Grundschober (1987),
Canas et al. (1989)
0.000006 Hamburger, pan fried, 85 g IQ, 6.38 ng 1.65b(19.6) TAS (1989), Knize et al. (1994)
0.000005 Hexachlorobenzene: daily U.S. avg Hexachlorobenzene, 14 ng 3.86 (65.1) FDA (1991a)
0.000001 Lindane: daily U.S. avg (1990) Lindane, 32 ng (—) 30.7 FDA (1991a)
0.0000004 PCNB: daily U.S. avg (1990) PCNB (Quintozene), 19.2 ng (—) 71.1 FDA (1991a)
0.0000001 Chlorobenzilate: daily U.S. avg (1989)dChlorobenzilate, 6.4 ng (—) 93.9 FDA (1991a)
0.00000008 Captan: daily U.S. avg (1990) Captan, 115 ng 2080 (2110) FDA (1991a)
0.00000001 Folpet: daily U.S. avg (1990) Folpet, 12.8 ng (—) 1550 FDA (1991a)
<0.00000001 Chlorothalonil: daily U.S. avg (1990) Chlorothalonil, <6.4 ng 828c(—) FDA (1991a), EPA (1987a)
Chemicals that occur naturally in foods are in bold face. Daily human exposure: Reasonable daily intakes are used to facilitate comparisons. The calculations
assume a daily dose for a lifetime. Possible hazard: The human dose of rodent carcinogen is divided by 70 kg to give a mg/kg/day of human exposure, and this
dose is given as the percentage of the TD50 in the rodent (mg/kg/day) to calculate the human exposure/rodent potency (HERP) index. TD50 values used in the
HERP calculation are averages calculated by taking the harmonic mean (see Section 38.8) of the TD50s of the positive tests in that species from the Carcinogenic
Potency Database. Average TD50 values, have been calculated separately for rats and mice, and the more potent value is used for calculating possible hazard.
a·, no data in the CPDB; a number in parentheses indicates a TD50 value not used in the HERP calculation because the TD50 is less potent than in the other
species; (—), negative in cancer tests; (+), positive cancer test(s) not suitable for calculating a TD50.
bThe TD50 harmonic mean was estimated for the base chemical from the hydrochloride salt.
cAdditional data from the EPA that were not in the CPDB were used to calculate this TD50 harmonic mean.
dNo longer contained in any registered pesticide product (EPA, 1998).
posure amounts are for concentrations of a chemical in an
individual food (i.e., foods for which data are available on con-
centration and average consumption).
Table 38.5 indicates that many ordinary foods would not
pass the regulatory criteria used for synthetic chemicals if the
same methodology were used for both naturally occurring and
synthetic chemicals. For many natural chemicals, the HERP
values are in the top half of the table, even though natural chem-
icals are markedly underrepresented because so few have been
tested in rodent bioassays. We will discuss several categories
of exposure and indicate that mechanistic data are available for
some chemicals, which suggest that the possible hazard may
not be relevant to humans or would be low if nonlinearity or a
threshold were taken into account in risk assessment.
810 CHAPTER 38 Pesticide Residues in Food and Cancer Risk: A Critical Analysis
Occupational Occupational and pharmaceutical exposures
to some chemicals have been high, and many of the single
chemical agents or industrial processes evaluated as human car-
cinogens have been identified by historically high exposures
in the workplace (Tomatis and Bartsch, 1990; IARC, 1971–
1999). HERP values rank at the top of Table 38.5 for past
chemical exposures in some occupations to ethylene dibromide,
1,3-butadiene, tetrachloroethylene, formaldehyde, acrylonitrile,
trichloroethylene, and methylene chloride. When exposures are
high, the margin of exposure from the carcinogenic dose in
rodents is low. The issue of how much human cancer can be
attributed to occupational exposure has been controversial, but
a few percent seems a reasonable estimate (Ames et al., 1995).
In another analysis, we have used permitted exposure lim-
its (PELs), recommended in 1989 by the U.S. Occupational
Safety and Health Administration (OSHA), as surrogates for
actual exposures and compared the permitted daily dose rate
for workers, with the TD50 in rodents [PERP (permitted ex-
posure/rodent potency) index] (Gold et al., 1987b, 1994a). We
found that the PELs for 9 chemicals were greater than 10%
of the rodent carcinogenic dose and for 27 they were between
1 and 10% of the rodent dose. The 1989 PELS were vacated
by the Supreme Court because of a lack of risk assessment on
each individual chemical. For the PELs that are currently the
legal standard, PERP values for 14 chemicals are greater than
10%. For trichloroethylene, we recently conducted an analysis
based on an assumed cytotoxicmechanism of action and PBPK-
effective dose estimates defined as peak concentrations. Our
estimates indicate that occupationalrespiratory exposures at the
PEL for trichloroethylene would produce metabolite concentra-
tions that exceed an acute no observed effect level (NOEL) for
hepatotoxicity in mice. On this basis, the OSHA PEL is not
expected to be protective. In comparison the EPA maximum
concentration limit (MCL) in drinking water of 5 µg/l, based
on a linearized multistage model, is more stringent than our es-
timate of an MCL based on a 1000-fold safety (uncertainty)
factor, which is 210 µg/l (Bogen and Gold, 1997).
Pharmaceuticals Some pharmaceuticals that are used chron-
ically are clustered near the top of the HERP ranking (e.g.,
phenobarbital, clofibrate, and fluvastatin). In Table 38.3, we re-
ported that 49% of the drugs in the PDR with cancer test data
are positive in rodent bioassays (Davies and Monro, 1995), as
are 44% of drug submissions to the FDA (Contrera et al., 1997).
Most drugs, however, are used for only short periods, and the
HERP values for the rodent carcinogens would not be compa-
rable to the chronic, long-term administration used in HERP.
Assuming a hypothetical lifetime exposure at therapeutic doses
(i.e., not averaged over a lifetime), the HERP values would be
high—for example, phenacetin (0.3%), metronidazole (5.6%),
and isoniazid (14%).
Herbal supplements have recently developed into a large
market in the United States; they have not, however, been a
focus of carcinogenicity testing. The FDA regulatory require-
ments for safety and efficacy that are applied to pharmaceutical
drugs do not pertain to herbal supplements under the 1994 Di-
etary Supplements and Health Education Act (DSHEA), and
few have been tested for carcinogenicity. Those that are rodent
carcinogens tend to rank highin HERP because, similar to some
pharmaceutical drugs, the recommended dose is high relative
to the rodent carcinogenic dose. Moreover, under DSHEA, the
safety criteria that have been used for decades by the FDA for
food additives that are “generally recognized as safe” (GRAS)
are also not applicable to dietary supplements (Burdock, 2000)
even though supplements are used at higher doses. The NTP is
currently testing several herbs or chemicals in herbs.
Comfrey is a medicinal herb whose roots and leaves have
been shown to be carcinogenic in rats. The formerly recom-
mended dose of 9 daily comfrey–pepsin tablets has a HERP
value of 6.2%. Symphytine, a pyrrolizidine alkaloid plant pesti-
cide that is present in comfrey–pepsin tablets and comfrey tea,
is a rodent carcinogen; the HERP value for symphytine is 1.3%
in the comfrey pills and 0.03% in comfrey herb tea. Comfrey
pills are no longer widely sold, but are available on the World
Wide Web. Comfrey roots and leaves can be bought at health
food stores and on the Web and can thus be used for tea, al-
though comfrey is recommended for topical use only in the
PDR for Herbal Medicines (Gruenwald et al., 1998). Poison-
ing epidemics by pyrrolizidine alkaloids have occurred in the
developing world. In the United States, poisonings, including
deaths, have been associated with use of herbal teas containing
comfrey (Huxtable, 1995). Over 200 pyrrolizidine alkaloids are
present in more than 300 plant species (Prakash et al., 1999).
Up to 3% of flowering plant species contain pyrrolizidine al-
kaloids (Prakash et al., 1999). Several pyrrolizidine alkaloids
have been tested chronically in rodent bioassays and are car-
cinogenic (Gold et al., 1997b).
Dehydroepiandrosterone (DHEA) and DHEA sulfate are the
major secretion products of adrenal glands in humans and are
precursors of androgenic and estrogenic hormones (Oelkers,
1999; van Vollenhoven, 2000). DHEA is manufactured and sold
widely for a variety of purposes includingthe delay of aging. In
rats, DHEA induces liver tumors (Rao et al., 1992a; Hayashi
et al., 1994), and the HERP value for the recommended human
dose of one daily capsule containing 25 mg DHEA is 0.5%. The
mechanism of liver carcinogenesis in rats is peroxisome prolif-
eration, similar to clofibrate (Ward et al., 1998; Woodyatt et al.,
1999). DHEA also inhibited the development of tumors of the
rat testis (Rao et al., 1992b) and rat and mouse mammary gland
(Schwartz et al., 1981; McCormick et al., 1996). A recent re-
view of clinical, experimental, and epidemiological studies con-
cluded that late promotion of breast cancer in postmenopausal
women may be stimulated by prolonged intake of DHEA (Stoll,
1999); however, the evidence for a positive association in post-
menopausal women between serum DHEA levels and breast
cancer risk is conflicting (Bernstein et al., 1990; Stoll, 1999).
Natural Pesticides Natural pesticides, because few have been
tested, are markedly underrepresented in our HERP analy-
sis. More important, for each plant food listed, there are
about 50 additional untested natural pesticides. Although about
38.5 The HERP Ranking of Possible Carcinogenic Hazards 811
10,000 natural pesticides and their breakdown products oc-
cur in the human diet (Ames et al., 1990b), only 71 have
been tested adequately in rodent bioassays (Table 38.1). Av-
erage exposures to many natural-pesticide rodent carcinogens
in common foods rank above or close to the median in our
HERP table (Table 38.5), ranging up to a HERP of 0.1%.
These include caffeic acid (in coffee, lettuce, tomato, apple,
potato, celery, carrot, plum, and pear); safrole (in spices and
formerly in natural root beer before it was banned); allyl iso-
thiocyanate (in mustard); d-limonene (in mango, orange juice,
black pepper); coumarin (in cinnamon); and hydroquinone,
catechol, and 4-methylcatechol (in coffee). Some natural pesti-
cides in the commonly eaten mushroom (Agaricus bisporus)are
rodent carcinogens (glutamyl-p-hydrazinobenzoate, p-hydra-
zinobenzoate), and the HERP based on feeding whole mush-
rooms to mice is 0.02%. For d-limonene, no human risk is
anticipated because tumors are induced only in male rat kidney
tubules with involvement of α2u -globulin nephrotoxicity, which
does not appear to be relevant for humans, as discussed in Sec-
tion 38.2 (Hard and Whysner, 1994; International Agency for
Research on Cancer, 1993; Rice et al., 1999; U.S. Environmen-
tal Protection Agency, 1991a).
Synthetic Pesticides Synthetic pesticides currently in use
that are rodent carcinogens in the CPDB and that are quantita-
tively detected by the FDA Total Diet Study (TDS) as residues
in food are all included in Table 38.5. Many are at the very
bottom of the ranking; however, HERP values are about at the
median for ethylene thiourea (ETU), UDMH (from Alar) before
its discontinuance, and DDT before its ban in the United States
in 1972. These three synthetic pesticides rank below the HERP
values for many naturally occurring chemicals that are common
in the diet. The HERP values in Table 38.5 are for residue intake
by females 65 and older, because they consume higher amounts
of fruits and vegetables than other adult groups, thus maximiz-
ing the exposure estimate to pesticide residues. We note that for
pesticide residues in the TDS, average consumption estimates
for children (mg/kg/day in 1986–1991) are within a factor of
3 of the adult consumption (mg/kg/day), greater in adults for
some pesticides, and greater in children for others (U.S. Food
and Drug Administration, 1993b).
DDT and similar early pesticides have been a concern be-
cause of their unusual lipophilicity and persistence, even though
there is no convincing epidemiological evidence of a carcino-
genic hazard to humans (Key and Reeves, 1994) and although
natural pesticides can also bioaccumulate. In a recently com-
pleted 24-year study in which DDT was fed to rhesus and
cynomolgus monkeys for 11 years, DDT was not evaluated as
carcinogenic (Takayama et al., 1999; Thorgeirsson et al., 1994)
despite doses that were toxic to both liver and central nervous
system. However, the protocol used few animals anddosing was
discontinued after 11 years, which may have reduced the sensi-
tivity of the study (Gold et al., 1999). The HERP value for DDT
residues in food before the ban was 0.0008%.
Current U.S. exposureto DDT and its metabolites is in foods
of animal origin, and the HERP value is low, 0.00008%. DDT
is often viewed as the typically dangerous synthetic pesticide
because it concentrates in adipose tissue and persists for years.
DDT was the first synthetic pesticide; it eradicated malaria from
many parts of the world, including the United States, and was
effective against many vectors of disease such as mosquitoes,
tsetse flies, lice, ticks, and fleas. DDT was also lethal to many
crop pests and significantly increased the supply and lowered
the cost of fresh, nutritious foods, thus making them accessible
to more people. A 1970 National Academy of Sciences report
concluded: “In little more than two decades DDT has prevented
500 million deaths due to malaria, that would otherwise have
been inevitable” (National Academy of Sciences, 1970).
DDT is unusual with respect to bioconcentration, and be-
cause of its chlorine substituents it takes longer to degrade
in nature than most chemicals; however, these are properties
of relatively few synthetic chemicals. In addition, many thou-
sands of chlorinated chemicals are produced in nature (Gribble,
1996). Natural pesticides can also bioconcentrate if they are fat
soluble. Potatoes, for example, naturally contain the fat-soluble
neurotoxins solanine and chaconine (Ames et al., 1990a; Gold
et al., 1997a), which can be detected in the bloodstream of all
potato eaters. High levels of these potato neurotoxins have been
shown to cause birth defects in rodents (Ames et al., 1990b).
The HERP value for ethylene thiourea (ETU), a breakdown
product of certain fungicides, is the highest among the syn-
thetic pesticide residues (0.002%), which is at the median of
the ranking. The HERP would be about 10 times lower if the
potency value of the EPA were used instead of our TD50;the
EPA combined rodent results from more than one experiment,
including one in which ETU was administered in utero, and ob-
tained a weaker potency value (U.S. Environmental Protection
Agency, 1992). (The CPDB does not include in utero expo-
sures.) Additionally, the EPA has recently discontinued some
uses of fungicides for which ETU is a breakdown product; and
therefore exposure levels and HERP values would be lower.
In 1984, the EPA banned the agricultural use of ethylene
dibromide (EDB), the main fumigant in the United States, be-
cause of the residue levels found in grain (HERP =0.0004%).
This HERP value ranks low, compared to the HERP of 140%
for the high exposures to EDB that some workers received in the
1970s which is at thetop of the ranking (Gold et al., 1992). Two
other pesticides in Table 38.5, toxaphene (HERP =0.0002%)
and chlorobenzilate (HERP =0.0000001%), have been can-
celled (Ames and Gold, 1991; U.S. Environmental Protection
Agency, 1998).
Most residues of synthetic pesticides have HERP values
below the median. In descending order of HERP, these are
carbaryl, toxaphene, dicofol, lindane, PCNB, chlorobenzilate,
captan, folpet, and chlorothalonil. Some of the lowest HERP
values in Table 38.5 are for the synthetic pesticides, captan,
chlorothalonil, and folpet, which were also evaluated in 1987
by the National Research Council (NRC) and were considered
by the NRC to have a human cancer risk above 106(National
Research Council, 1987). The contrast between the low HERP
values for synthetic pesticide residues in our ranking and the
higher NRC risk estimates is examined in Section 38.6.
812 CHAPTER 38 Pesticide Residues in Food and Cancer Risk: A Critical Analysis
Cooking and Preparation of Food and Drink Cooking and
preparation of food can also produce chemicals that are rodent
carcinogens. Alcoholic beverages cause cancer in humans in
the liver, esophagus, and oral cavity. The HERP values in Ta-
ble 38.5 for alcohol in beer (2.1%) and wine (0.5%) are high in
the ranking. Ethyl alcohol is one of the least potent rodent car-
cinogens in the CPDB, but the HERP is high because of high
concentrations in alcoholic beverages and high U.S. consump-
tion. Another fermentation product, urethane (ethyl carbamate),
has a HERP value of 0.00001% for average beer consumption
and 0.00007% for average bread consumption (as toast).
Cooking food is plausible as a contributor to cancer. A wide
variety of chemicals are formed during cooking. Rodent car-
cinogens formed include furfural and similar furans, nitros-
amines, polycyclic hydrocarbons, and heterocyclic amines.
Furfural, a chemical formed naturally when sugars are heated,
is a widespread constituent of food flavor. The HERP value
for naturally occurring furfural in the average consumption of
coffee is 0.02% and in white bread it is 0.004%. Furfural is
also used as a commercial food additive, and the HERP for
total average U.S. consumption as an additive is much lower
Nitrosamines in food are formed by cooking from ni-
trite or nitrogen oxides (NOx) and amines. Tobacco smoking
and smokeless tobacco are a major source of nonoccupa-
tional exposure to nitrosamines that are rodent carcinogens
[N-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyri-
dyl)-1-(butanone)] (Hecht and Hoffmann, 1998). Most expo-
sure to nitrosamines in the diet is for chemicals that are
not carcinogenic in rodents (Hecht and Hoffmann, 1998; Li-
jinsky, 1999). The nitrosamines that are carcinogenic are
potent carcinogens (Table 38.5), and it has been estimated
that in several countries humans are exposed to about 0.3–
1µg/day (National Academy of Sciences, 1981; Tricker
and Preussmann, 1991), primarily N-nitrosodimethylamine
(DMN), N-nitrosopyrrolidine, and N-nitrosopiperidine. The
largest exposure is to DMN in beer: Concentrations declined
more than 30-fold after 1979 (HERP =0.01%) when it was re-
ported that DMN was formed by the direct-fired drying of malt,
and the industry modified the process to indirect firing (Glória
et al., 1997). By the 1990s, the HERP was 0.0003% (Glória
et al., 1997). The HERP values for the average consump-
tion of bacon are lower: DMN =0.0005%, DEN =0.0006%,
and NPYR =0.0004%. DEN induced liver tumors in rhesus
and cynomolgus monkeys and tumors of the nasal mucosa in
bush babies (Thorgeirsson et al., 1994). In a study of DMN
in rhesus monkeys, no tumors were induced; however, the ad-
ministered doses produced toxic hepatitis, and all animals died
early. Thus, the test was not sensitive because the animals may
not have lived long enough to develop tumors (Gold et al., 1999;
Thorgeirsson et al., 1994).
A variety of mutagenic and carcinogenic heterocyclic amines
(HAs) are formed when meat, chicken, and fish are cooked, par-
ticularly when charred. Compared to other rodent carcinogens,
there is strong evidence of carcinogenicity for HAs in terms of
positivity rates and multiplicity of target sites; however, con-
cordance in target sites between rats and mice for these HAs is
generally restricted to the liver (Gold et al., 1994b). Under usual
cooking conditions, exposures to HAs are in the low ppb range,
and the HERP values for pan-fried hamburger are low. The
HERP value for PhIP is 0.00006%, for MeIQx it is 0.00003%,
and for IQ it is 0.000006%. Carcinogenicity of the three HAs
in the HERP table, IQ, MeIQx, and PhIP, has been investigated
in studies in cynomolgus monkeys. IQ rapidly induced a high
incidence of hepatocellular carcinoma (Adamson et al., 1994).
MeIQx, which induced tumors at multiple sites in rats and mice
(Gold et al., 1997c), did not induce tumors in monkeys (Ogawa
et al., 1999). The PhIP study is in progress. Metabolism studies
indicate the importance of N-hydroxylation in the carcinogenic
effect of HAs in monkeys (Snyderwine et al., 1997). IQ is
activated via N-hydroxylation and forms DNA adducts; the N-
hydroxylation of IQ appears to be carried out largely by hepatic
CYP3A4 and/or CYP2C9/10, and not by CYP1A2; whereas
the poor activation of MeIQx appears to be due to a lack of
expression of CYP1A2 and an inability of other cytochromes
P450, such as CYP3A4 and CYP2C9/10, to N-hydroxylate the
quinoxalines. PhIP is activated by N-hydroxylation in monkeys
and forms DNA adducts, suggesting that it might turn out to
have a carcinogenic effect (Ogawa et al., 1999; Snyderwine et
al., 1997).
Food Additives Food additives that are rodent carcinogens
can be either naturally occurring (e.g., allyl isothiocyanate,
furfural, and alcohol) or synthetic (e.g., BHA and saccharin;
Table 38.5). The highest HERP values for average dietary ex-
posures to synthetic rodent carcinogens in Table 38.5 are for
exposures in the early 1970s to BHA (0.01%) and saccharin in
the 1970s (0.005%). Both are nongenotoxic rodent carcinogens
for which data on the mechanism of carcinogenesis strongly
suggest that there would be no risk to humans at the levels found
in food.
BHA is a phenolic antioxidant that is “generally regarded
as safe” (GRAS) by the FDA. By 1987, after BHA was shown
to be a rodent carcinogen, its use declined sixfold (HERP =
0.002%) (U.S. Food and Drug Administration, 1991b);this was
due to voluntary replacement by other antioxidants and to the
fact that the use of animal fats and oils, in which BHA is pri-
marily used as an antioxidant, has consistently declined in the
United States. The mechanistic and carcinogenicity results on
BHA indicate that malignant tumors were induced only at a
dose above the MTD at which cell division was increased in
the forestomach, which is the only site of tumorigenesis; the
proliferation is only at high doses and is dependent on contin-
uous dosing until late in the experiment (Clayson et al., 1990).
Humans do not have a forestomach. We note that the dose–
response relationship for BHA curves sharply upward, but the
potency value used in HERP is based on a linear model; if the
California EPA potency value (which is based on a linearized
multistage model) were used in HERP instead of the TD50,the
HERP values for BHA would be 25 times lower (California
Environmental Protection Agency, 1994). A recent epidemio-
logical study in the Netherlands found no association between
38.5 The HERP Ranking of Possible Carcinogenic Hazards 813
BHA consumption and stomach cancer in humans (Botterweck
et al., 2000).
Saccharin, which has largely been replaced by other sweet-
eners, has been shown to induce tumors in rodents by a mech-
anism that is not relevant to humans. Recently, both the NTP
and the IARC reevaluatedthe potential carcinogenic risk of sac-
charin to humans. The NTP delisted saccharin in its Report on
Carcinogens (U.S. National Toxicology Program, 2000a), and
the IARC downgraded its evaluation to Group 3, “not classi-
fiable as to carcinogenicity to humans” (International Agency
for Research on Cancer, 1971–1999). There is convincing ev-
idence that the induction of bladder tumors in rats by sodium
saccharin requires a high dose and is related to the develop-
ment of a calcium phosphate–containing precipitate in the urine
(Cohen, 1995a), which is not relevant to human dietary expo-
sures. In a recently completed 24-year study by the NCI, rhesus
and cynomolgus monkeys were fed a dose of sodium saccharin
that was equivalent to 5 cans of diet soda daily for 11 years
(Thorgeirsson et al., 1994). The average daily dose rate of
sodium saccharin (mg/kg/day) was about 100 times lower than
the dose that was carcinogenic to rats (Gold et al., 1997c, 1999).
There was no carcinogenic effect in monkeys. There was also
no effect on the urine or urothelium, no evidence of increased
urothelial cell proliferation or of formation of solid material in
the urine (Takayama et al., 1998). One would not expect to find
a carcinogenic effect under the conditions of the monkey study
because of the low dose administered. Additionally, however,
there may be a true species difference because primate urinehas
a low concentration of protein and is less concentrated (lower
osmolality) than rat urine (Takayama et al., 1998). Human urine
is similar to monkey urine in this respect (Cohen, 1995a).
For three naturally occurring chemicals that are also pro-
duced commercially and used as food additives, average ex-
posure data are available and they are included in Table 38.5.
The HERP values are as follows: For furfural, the HERP value
for the natural occurrence is 0.02% compared to 0.00006% for
the additive; for d-limonene, the natural occurrence HERP is
0.1% compared to 0.003% for the additive; and for estragole,
the HERP is 0.00005% for both the natural occurrence and the
Safrole is the principal component (up to 90%) of oil of sas-
safras. It was formerlyused as the main flavor ingredientin root
beer. It is also present in the oils of basil, nutmeg, and mace (Ni-
jssen et al., 1996). The HERP value for average consumption of
naturally occurring safrole in spices is 0.03%. In 1960, safrole
and safrole-containing sassafras oils were banned from use as
food additivesin the United States (U.S. Foodand Drug Admin-
istration, 1960). Before 1960, for a person consuming a glass of
sassafras root beer per day for life, the HERP value would have
been 0.2% (Ames et al., 1987). Sassafras root can still be pur-
chased in health food stores and can therefore be used to make
tea (Heikes, 1994); the recipe is on the World Wide Web.
Mycotoxins Of the 23 fungal toxins tested for carcinogenic-
ity, 14 are positive (61%) (Table 38.3). The mutagenic mold
toxin, aflatoxin, which is found in moldy peanut and corn prod-
ucts, interacts with chronic hepatitis infection in human liver
cancer development (Qian et al., 1994). There is a synergistic
effect in the human liver between aflatoxin (genotoxic effect)
and the hepatitis B virus (cell division effect) in the induction
of liver cancer (Wu-Williams et al., 1992). The HERP value for
aflatoxin of 0.008% is based on the rodent potency. If the lower
human potency value calculated from epidemiological data by
the FDA were used instead, the HERP would be about 10-fold
lower (U.S. Food and Drug Administration, 1993b). Biomarker
measurements of aflatoxin in populations in Africa and China,
which have high rates of hepatitis B and C viruses and liver
cancer, confirm that those populations are chronically exposed
to high levels of aflatoxin (Groopman et al., 1992; Pons, 1979).
Liver cancer is unusual in the United States. Hepatitis viruses
can account for half of liver cancer cases among non-Asians
and even more among Asians in the United States (Yu et al.,
Ochratoxin A, a potent rodent carcinogen (Gold and Zeiger,
1997), has been measured in Europe and Canada in agricul-
tural and meat products. An estimated exposure of 1 ng/kg/day
would have a HERP value close to the median of Table 38.5
(International Life Sciences Institute, 1996; Kuiper-Goodman
and Scott, 1989).
Synthetic Contaminants Polychlorinated biphenyls (PCBs)
and tetrachlorodibenzo-p-dioxin (TCDD), which have been a
concern because of their environmental persistence and car-
cinogenic potency in rodents, are primarily consumed in foods
of animal origin. In the United States, PCBs are no longer
used, but some exposure persists. Consumption in food in the
United States declined about 20-fold between 1978 and 1986
(Gartrell et al., 1986; Gunderson, 1995). The HERP value for
the most recent reporting of the FDA Total Diet Study (1984–
1986) is 0.00008%, toward the bottom of the ranking, and far
below many values for naturally occurring chemicals in com-
mon foods. It has been reported that some countries may have
higher intakes of PCBs than the United States (World Health
Organization, 1993).
TCDD, the most potent rodent carcinogen, is produced nat-
urally by burning when chloride ion is present, for example, in
forest fires or wood burning in homes. The EPA (U.S. Environ-
mental Protection Agency, 2000) proposes that the source of
TCDD is primarily from the atmosphere directly from emis-
sions (e.g., incinerators) or indirectly by returning dioxin to
the atmosphere (U.S. Environmental Protection Agency, 2000).
TCDD bioaccumulates through the food chain because of its
lipophilicity, and more than 95% of human intake is from an-
imal fats in the diet (U.S. Environmental Protection Agency,
2000). Dioxin emissions decreased by 80% from 1987 to 1995,
which the EPA attributes to reduced emissions from incin-
eration of medical and municipal waste (U.S. Environmental
Protection Agency, 2000).
The HERP value of 0.0004% for average U.S. intake of
TCDD (U.S. Environmental Protection Agency, 2000) is be-
low the median of the values in Table 38.6. Recently, the EPA
814 CHAPTER 38 Pesticide Residues in Food and Cancer Risk: A Critical Analysis
Table 38.6
Tumor Incidence Data Used in Recalculations of Carcinogenic Potency for 19 Chemicals in the NRC Report
Weeks Sex– Dose groups TD50
Pesticideaon test speciesbTarget organ (mg/kg/day)cTumor incidence (mg/kg/day)
AcephateNA(Cnq)105 FM Liver 0, 7.5, 37.5, 150 1/62, 3/61, 0/62, 15/61 499
AlachlorB2(MOE)110 FR Nasal Turbinate 0, 0.5, 2.5, 15 0/44, 0/47, 0/44, 15/45 36.8
MR 0/42, 0/42, 1/47, 14/48
AsulamNA(Cnq)108 MR Thyroid gland 0, 36, 180, 953 0/43, 9/43, 7/43, (2/40)d724
AzinphosmethylD(E)114eMR Thyroid gland 0, 3.9, 7.8 1/9, 10/44, 12/43 31.6
BenomylCq 104 FM Liver 0, 75, 225, 1130 1/74, 9/70, 20/75, 15/75 4,400
CaptafolB2 104 FR Liver 0, 2.8, 12.1, 54.8 4/50, 2/49, 3/50, 17/50 202
MR Kidney 1/50, 1/50, 0/50, 7/50
CaptanB2 113 FM Digestive tract 0, 879, 1480, 2370 3/80, 26/80, 21/80, 29/80 4,480
MM 3/80, 19/80, 22/80, 39/80
95 FM 0, 15, 60, 120, 900 0/100, 1/100, 3/100, 4/100, 9/100
MM 0/100, 7/100, 1/100, 1/100, 7/100
ChlordimeformB2 104 FM Hematopoietic 0, 0.3, 3, 30, 75 3/38, 1/35, 11/42, 31/39, 34/41 21.7
MM 3/47, 1/46, 12/46, 32/47, 40/47
ChlorothalonilNA(B2)(MOE)129 FR Kidney 0, 40, 80, 175 0/59, 2/60, 7/57, 19/58 566
CypermethrinCq(Cnq)101 FM Lung 0, 15, 60, 240 12/127, 6/64, 8/64, 14/61 954
FolpetB2 113 FM Digestive tract 0, 96, 515, 1280 0/104, 1/80, 8/80, 41/80 1,910
MM 0, 93, 502, 1280 1/104, 2/80, 8/80, 41/80
Fosetyl AlCq(Cnq)(Unclassified)104 MR Adrenal gland 0, 100, 400, 1510 6/80, 7/78, 16/79, (18/80)d1,860
GlyphosateCq(E)104 MM Kidney 0, 150, 750, 4500 1/49, 0/49, 1/50, 3/50 62,000
LinuronCq(Cnq)104 MR Testis 0, 2.5, 6.25, 31.3 4/70, 9/69, 20/70, 37/70 28.1
MetolachlorCq(Cnq)(MOE)104 FR Liver 0, 1.5, 15, 150 0/60, 1/60, 2/60, 7/60 839
OryzalinCq 104 FR Skin 0, 15, 45, 135 1/60, 2/60, 4/60, 9/60 394
MR 5/60, 6/60, 6/60, 24/59
OxadiazonB2(Cq)105 FM Liver 0, 15, 45, 150, 300 4/56, 13/61, 18/64, 27/55, 32/57 213
MM 20/64, 40/67, 52/69, 44/65, 28/35
ParathionCq(Cnq)112 FR Adrenal gland 0, 1.15, 2.25 1/10, 6/47, 13/42 7.95
MR 0, 1.6, 3.15 0/9, 7/49, 11/46
PermethrinCq 104 FM Lung 0, 3, 375, 750 15/71, 24/68, 35/68, 44/69 717
aEPA weight-of-evidence evaluation reported as superscript. If more than one classification is reported, the first values are from the NRC report and values
in parentheses are from the EPA’s revised evaluations since 1987 (Burnam, 2000; Irene, 1995). B2: Sufficient evidence of carcinogenicity from animal studies
with inadequate or no epidemiologic data—probable human carcinogen. Cq: Limited evidence of carcinogenicity from animal studies in the absence of human
data—possible human carcinogen (quantifiable). Cnq: Limited evidence (not quantified by the EPA, i.e., no q
1). D: Human and animal data are either inadequate
or absent—not classifiable as to human carcinogenicity. E: Evidence of noncarcinogenicity to humans. NA indicates that the chemical was not classifiedatthe
time of the NRC report. MOE: The Health Effects Division Carcinogenicity Peer Review Committee (HCPRC) recommended under the newly proposed EPA
guidelines a margin-of-exposure approach for risk assessment for these three chemicals: alachlor, chlorothalonil, and metolachlor. For alachlor, the current Office
of Pesticide Programs (OPP) classification is “Likely (high doses), Not Likely (low doses). ” For chlorothalonil, the classification is “Likely” with recommendation
for a nonlinear approach to risk assessment. Unclassified: For fosetyl Al, the HCPRC concluded that it “was not amenable to classification using current Agency
cancer guidelines. The HCPRC concluded that pesticidal use of fosetyl-Al is unlikely to pose a carcinogenic hazard to humans” (Burnam, 2000). Captafol and
chlordimeform uses have been canceled (U.S. Environmental Protection Agency, 1998).
bFM, female mouse; MM, male mouse; FR, female rat; MR, male rat. If more than one group is reported, the potency calculation is a geometric mean of the TD50
for the experiments in this table only.
cUnless mg/kg/day are given in the EPA memorandum, doses are converted from ppm to mg/kg body weight/day by standard EPA conversion factors: 0. 05 for
rats and 0. 15 for mice. All chemicals were administered in the diet.
dDoses in parentheses were not used in the calculation of either the TD50 or the EPA q
1. For fosetyl Al, the adrenal gland q
1most closely replicated the NRC q
in later EPA documents, urinary bladder was the target site and results were not considered appropriate for quantification (Quest et al., 1991).
eDosing was only for 80 weeks.
38.5 The HERP Ranking of Possible Carcinogenic Hazards 815
has reestimated the potency of TCDD based on a change in the
dose-metric to body burden in humans (rather than intake) (U.S.
Environmental Protection Agency, 2000) and a reevaluation of
tumor data in rodents (which determined two-thirds fewer liver
tumors) (Goodman and Sauer, 1992). Using this EPA potency
for HERP would put TCDD at the median of HERP values in
Table 38.6, 0.002%.
TCDD exerts many of its harmful effects in experimental
animals through binding to the Ah receptor (AhR) and does
not have effects in the AhR knockout mouse (Birnbaum, 1994;
Fernandez-Salguero et al., 1996). A wide variety of natural
substances also bind to the AhR (e.g., tryptophan oxidation
products), and insofar as they have been examined, they have
similar properties to TCDD (Ames et al., 1990b), including
inhibition of estrogen-induced effects in rodents (Safe et al.,
1998). For example, a variety of flavones and other plant sub-
stances in the diet and their metabolites also bind to the AhR
[e.g., indole-3-carbinol (I3C)]. I3C is the main breakdown com-
pound of glucobrassicin, a glucosinolate that is present in large
amounts in vegetables of the Brassica genus, including broc-
coli, and gives rise to the potent Ah binder indole carbazole
(Bradfield and Bjeldanes, 1987). The binding affinity (greater
for TCDD) and the amounts consumed (much greater for di-
etary compounds) both need to be considered in comparing
possible harmful effects. Some studies provide evidence of
enhancement of carcinogenicity by I3C (Dashwood, 1998). Ad-
ditionally, both I3C and TCDD, when administered to pregnant
rats, resulted in reproductive abnormalities in male offspring
(Wilker et al., 1996). Currently, I3C is in clinical trials for
prevention of breast cancer (Kelloff et al., 1996a, b; U.S. Na-
tional Toxicology Program, 2000b) and is also being tested
for carcinogenicity in rodents by NTP (U.S. National Toxicol-
ogy Program, 2000b). I3C is marketed as a dietary supplement
at recommended doses about 30 times higher (Theranaturals,
2000) than present in the average Western diet (U.S. National
Toxicology Program, 2000b).
TCDD has received enormous scientific and regulatory at-
tention, most recently in an ongoing assessment by the EPA
(U.S. Environmental Protection Agency, 1994a, 1995a, 2000).
Some epidemiologic studies suggest an association with can-
cer mortality. In 1997 the IARC evaluated the epidemiological
evidence for carcinogenicity of TCDD in humans as limited
(International Agency for Research on Cancer, 1997). The
strongest epidemiological evidence was among highly exposed
workers for overall cancer mortality. There is no sufficient ev-
idence in humans for any particular target organ. Estimated
blood levels of TCDD in studies of those highly exposed
workers were similar to blood levels in rats in positive can-
cer bioassays (International Agency for Research on Cancer,
1997). In contrast, background levels of TCDD in humans are
about 100- to 1000-fold lower than in the rat study. The sim-
ilarities of worker and rodent blood levels and the mechanism
of the AhR in both humans and rodents were considered by
the IARC when it evaluated TCDD as a Group 1 carcinogen
in spite of only limited epidemiological evidence. The IARC
also concluded that “Evaluation of the relationship between the
magnitude of the exposure in experimental systems and the
magnitude of the response, (i.e., dose–response relationships)
do not permit conclusions to be drawn on the human health risks
from background exposures to 2,3,7,8-TCDD.” The NTP Re-
port on Carcinogens recently evaluated TCDD in an addendum
to the Ninth Report on Carcinogens as a known human car-
cinogen (U.S. National Toxicology Program, 2000a, 2001). The
EPA draft final report (U.S. Environmental Protection Agency,
2000) characterized TCDD as a “human carcinogen,” but con-
cluded that “there is no clear indication of increased disease in
the general population attributable to dioxin-like compounds”
(U.S. Environmental Protection Agency, 2000). Possible lim-
itations of data or scientific tools were given by the EPA as
possible reasons for the lack of observed effects.
In summary, the HERP ranking in Table 38.5 indicates that
when synthetic pesticide residues in the diet are ranked on an
index of possible carcinogenic hazard and compared to the
ubiquitous exposures to rodent carcinogens, they rank low.
Widespread exposures to naturally occurring rodent carcino-
gens cast doubt on the relevance to human cancer of low-level
exposures to synthetic rodent carcinogens. In regulatory efforts
to prevent human cancer, the evaluation of low-level exposures
to synthetic chemicals has had a high priority. Our results in-
dicate, however, that a high percentage of both natural and
synthetic chemicals are rodent carcinogens at the MTD, that
tumor incidence data from rodent bioassays are not adequate to
assess low-dose risk, and that there is an imbalance in testing of
synthetic chemicals compared to natural chemicals. There is an
enormous background of natural chemicals in the diet that rank
high in possible hazard, even though so few have been tested
in rodent bioassays. In Table 38.5, 90% of the HERP values
are above the level that would approximate a regulatory vir-
tually safe dose of 106if a qualitative risk assessment were
Caution is necessary in drawing conclusions from the oc-
currence in the diet of natural chemicals that are rodent car-
cinogens. It is not argued here that these dietary exposures
are necessarily of much relevance to human cancer. In fact,
epidemiological results indicate that adequate consumption of
fruits and vegetables reduces cancer risk at many sites (Block
et al., 1992) and that protective factors like the intake of vita-
mins such as folic acid are important, rather than the intake of
individual rodent carcinogens.
The HERP ranking also indicates the importance of data on
the mechanism of carcinogenesis for each chemical. For sev-
eral chemicals, data have recently been generated that indicate
that exposures would not be expected to be a cancer risk to
humans at the levels consumed (e.g., saccharin, BHA, chloro-
form, d-limonene, discussed previously). Standard practice in
regulatory risk assessment for chemicals that induce tumors in
high-dose rodent bioassays has been to extrapolate risk to low
dose in humans by multiplying potency by human exposure.
Without data on the mechanism of carcinogenesis, however,
the true human risk of cancer at low dose is highly uncertain
and could be 0 (Ames and Gold, 1990; Clayson and Iverson,
1996; Gold et al., 1992; Goodman, 1994). Adequate risk assess-
816 CHAPTER 38 Pesticide Residues in Food and Cancer Risk: A Critical Analysis
ment from animal cancer tests requires more information for a
chemical about pharmacokinetics, mechanism of action, apop-
tosis, cell division, induction of defense and repair systems, and
species differences.
There are large disparities in the published cancer risk estimates
for synthetic pesticide residues in the U.S. diet. In our HERP
ranking in Table 38.5, the possible carcinogenic hazards of such
residues rank low when viewed in the broadened perspectiveof
exposures to naturally occurring chemicals that are rodent car-
cinogens. This section examines the extent to which disparities
in risk estimates are due to differences in potency estimation
from rodent bioassay data (q
1vs. TD50)ortodifferencesin
estimation of human dietary exposure (Theoretical Maximum
Residue Contribution vs. Total Diet Study). Our analysis is
based on risk estimates for 29 pesticides, herbicides, and fungi-
cides that were published by the National Research Council
(NRC) in its 1987 report, Regulating Pesticides in Food: The
Delaney Paradox (National Research Council, 1987). The NRC
used potency and exposure estimates of the EPA and concluded
that dietary risks for 23 pesticides were greater than one in a
million and therefore were not negligible. The methodologies to
estimate both potency and exposure differed between the NRC
and our HERP index, and these differences are examined here
to explain the difference in evaluation of possible cancer haz-
ards from synthetic pesticide residues. For both the EPA and
the HERP, risk estimation uses a linear extrapolation and is
simply potency ×dose. Our analysis below indicates that the
disparities in risk estimates are due to widely differentexposure
estimates, rather than to different estimated values of carcino-
genic potency.
The NRC report used the standard regulatory default method-
ology of the EPA to estimate risk, that is, to evaluate the weight
of evidence of carcinogenicity for a chemical from chronic
rodent bioassays and extrapolate risk using an upper bound
estimate of potency (q
1) and the linearized multistage model
(LMS) (Crump, 1984). Our HERP ranking used the TD50 (the
tumorigenic dose rate for 50% of test animals) as a measure
of potency, and the HERP index is a simple proportion: expo-
sure/potency (Section 38.4). To compare potency estimates, we
first attempted to reproduce the tumor site and incidence data
and the EPA q
1values reported by the NRC so that we could
use the correct data to estimate the TD50 and then compare the
two estimates. The NRC report did not present the tumor inci-
dence data, and for most experiments the results did not appear
in the general published literature. We obtained the results from
EPA memoranda and personal communications (Table 38.6).
The NRC report and the HERP ranking used two different
estimates of human exposure to pesticide residues in the diet.
The NRC used the EPA Theoretical Maximum Residue Con-
tribution (TMRC), whereas the HERP ranking used the FDA
Total Diet Study (TDS). The TMRC is a theoretical maximum
exposure, whereas exposure in the TDS is measured as dietary
residues in table-ready food. We assess the magnitude of the
differences between the two potency estimates q
1and TD50
when both use the same rodent results and then comparethe dif-
ferences between the two exposure estimates, TMRC and TDS,
in order to determine the basis for disparate risk estimates.
Since publication of the NRC report in 1987, the EPA has
made several changes in the risk estimates of some pesti-
cides. We discuss these changes, including: reevaluations of the
weight of evidence of carcinogenicity using rodent bioassay re-
sults, changes in whether risks should be quantified, changes in
exposure estimation, and proposed changes in risk assessment
The NRC, in Regulating Pesticides in Food: The Delaney Para-
dox (National Research Council, 1987), examined the potential
human cancer risk for a group of synthetic herbicides, in-
secticides, and fungicides that the EPA had classified as to
carcinogenicity based on rodent bioassay data. The NRC re-
ported the following EPA data: (1) carcinogenic potency (q
(2) an upper bound estimate of hypothetical, lifetime daily hu-
man exposure, TMRC; and (3) an upper bound estimate of
excess cancer risk over a lifetime, calculated as potency ×ex-
We obtained data from the EPA for 19 of the 26 chemicals
discussed by the NRC (Quest et al., 1993; U.S. Environ-
mental Protection Agency, 1984a, 1985–1988, 1985a, 1985b,
1986b, 1987b, 1988b, 1989b, 1989c, 1999a). We were not
able to identify the animal data used in the NRC report for
cryomazine, diclofop methyl, ethalfluralin, ethylene thiourea,
o-phenylphenol, pronamide, and terbutryn. To verify that we
had identified the correct rodent results, we attempted to repli-
cate the EPA q
1value for each of the 19 pesticides to define
the data set for our comparison of risk estimates. The Tox-Risk
program (Crump & Assoc.) was used to calculate q
1as the 95%
upper confidence limit on the linear term in the LMS, which
theoretically represents the slope of the dose–response curve
in the low-dose region. If it was not clear which target site had
been used by the EPA, we calculated more than one q
1and used
in our subsequent comparison of potency estimates whichever
data best reproduced the EPA q
1value. If the EPA memoran-
dum for a chemical stated that the q
1was the geometric mean
of two or more experiments, we used the same method.
The bioassay data that most accurately reproduced the EPA
1for each chemical are given in Table 38.6. Superscripts in-
dicate the EPA weight-of-evidence classification given in the
NRC report, followed by subsequent reevaluations of the clas-
Using the data in Table 38.6 with the Tox-Risk program,
overall there was good reproducibility in potency estimation
(Table 38.7). We were able to reproduce the EPA q
1value for
38.6 Pesticide Residues in Food: Investigation of Disparities in Cancer Risk Estimates 817
Table 38.7
Reproducibility of the EPA q
1Values Reported by the NRC
1reported by Recalculated q
1Recalculated q
Pesticide NRC (mg/kg/day)1(mg/kg/day)1EPA q
Chlorothalonil 2.4×1021.3×1020.5
Asulam 2.0×1021.4×1020.7
Oryzalin 3.4×1022.5×1020.7
Permethrin 3.0×1022.0×1020.7
Chlordimeform 9.4×1017.2×1010.8
Fosetyl Al 4.3×1033.7×1030.9
Captafol 2.5×1022.4×1021.0
Oxadiazon 1.3×1011.3×1011.0
Cypermethrin 1.9×1022.1×1021.1
Folpet 3.5×1033.8×1031.1
Linuron 3.3×1013.7×1011.1
Captan 2.3×1033.4×1031.5
Alachlor 6.0×1029.5×1021.6
Acephate 6.9×1031.3×1021.9
Benomyl 2.1×1034.6×1032.2
Metolachlor 2.1×1038.7×1034.1
Glyphosate 5.9×1054.8×1046.1
Parathion 1.8×1031.3×100720
Azinphosmethyl 1.5×1077.3×1014,900,000
Recalculated q
1uses the bioassay data in Table 38.6 and a linearized multistage model.
15 chemicals within a factor of 2.2, and for 17 within a fac-
tor of 6. The median ratio of the q
1reported by the NRC to
the recalculated q
1is 1.1. We could not approximate the q
for parathion or azinphosmethyl. The q
1published in the NRC
report for azinphosmethyl appears to be an error (W. Burnam,
Office of Pesticide Programs, EPA, personal communication).