Citation for this Web
Page: Lois Swirsky Gold, Bruce N. Ames, Thomas H. Slone.
Animal Cancer Tests and Human Cancer Risk: A Broad Perspective.
MOE.html, September 2008.
Carcinogenic Dose for 10% of Rodents (mg/kg/day)
Average Human Exposure (mg/kg/day)
- Results are rarely available in humans that identify chemicals
as a cause of human cancer. Therefore, to try and identify possible
hazards, chemicals have been tested in rodents at high, near toxic
doses daily for life, the Maximum Tolerated Dose (MTD), in order to
maximize the chance of increasing tumors in a small number of
animals. The MTD differs from one chemical to another by several
million-fold, and human exposures to rodent carcinogens vary by
more than a billion-fold. Both must be considered when evaluating
possible cancer hazards. Therefore, for each chemical exposure we
calculate how many fold lower the average human exposure is than
the dose to give rodents cancer — the Margin of Exposure
- The MOE for a chemical exposure is the ratio:
For example, a value of 1 means that the human
exposure level is the same as the dose that gave tumors in rodent
experiments. In a few unusual cases at the top of the graphic, the
MOE is less than 1, which indicates that human exposures were so
high that the rodent carcinogenic dose was actually lower than the
exposures to humans (e.g., occupational exposure to Vinyl chloride in the
1950’s, MOE=0.01). A value of 300 indicates that the rodent
carcinogenic dose is 300 times greater than the human intake (e.g.,
the naturally occurring chemical Safrole in spices in the total diet). A value
of 7,000,000 indicates that the rodent carcinogenic dose is 7
million times greater than the human exposure (e.g., the synthetic
pesticide Lindane in the total diet in 1990).
- The graphic on the right shows MOE values for different types
of human exposure reported by colors that are defined in the box at
top right. Human exposures to rodent carcinogens are ordered from
greatest possible human cancer hazard at the top to least possible
hazard at the bottom. Human exposures at the top are close to the
rodent carcinogenic dose while those towards the bottom are tiny
compared to the rodent carcinogenic dose; therefore, low MOE values
at the top of the graphic (lowest MOE) are of greatest concern for
possible cancer hazards.
- Symbols based on Human Relevance
↓↓ Results in
rodents are not relevant to human cancer risk.
↓ Results in rodents
would only be relevant to humans at toxic levels.
* Carcinogenic to humans at
A table in a popup window
reports details on human exposure, rodent cancer dose and reference
for each exposure in the graphic.
- The MOE for various human exposures ranges 100
- Many foods contain naturally-occurring chemicals that have been
shown to cause cancer in high dose rodent tests. Consumption of
natural chemicals in the diet (green on
the right) occurs in common foods at a range of MOE levels, and
many are much closer to the rodent cancer dose than synthetic
pesticide residues or pollutants (orange), which are far below the rodent cancer
dose. Exposures to natural chemicals include the chemical
constituents of fruits, vegetables or spices as well as the
products of cooking, such as chemicals in roasted coffee or
chemicals produced by cooking meat, fish, or French fries at high
- The common exposures to natural chemicals in the diet that
cause cancer in rodent tests cast doubt on the importance for human
cancer of synthetic pesticide residues or pollutants. We have
estimated that 99.9% of the chemicals humans are exposed to are
natural, and we find that they are as frequently positive in rodent
cancer tests as synthetic chemicals (see Proportion Of Chemicals That Are Carcinogenic in High Dose
Rodent Experiments). Many ordinary foods would not pass the
health criteria that have been used to regulate human exposures to
synthetic chemicals based on results of animal cancer tests.
- The graphic indicates that some historically high exposures in
the workplace (dark
blue) were close to the rodent administered dose,
including 3 marked with asterisks to indicate that epidemiological
results were positive at those levels; the MOE for these is less
than a factor of 2 of the rodent dose. Some pharmaceuticals
(red) are also close to the rodent dose,
but for clofibrate, phenobarbital, and gemfibrozil, the process of
tumor development in rodents has been evaluated as not relevant to
humans and there is no human risk (marked with ↓↓) (see
New Risk Assessment Paradigm).
“Rodent carcinogens” as defined by
high dose tests are ubiquitous. Public concern about cancer from
the low human exposures to synthetic pesticide residues or
pollutants does not seem warranted by the science.
Gold, L. S. et al. Misconceptions
About the Causes of Cancer.
Vancouver, Canada: Fraser Institute
(2002). Gold, L. S., et al.
Pesticide Residues in Food and
Cancer Risk: A Critical Analysis. In: Handbook of Pesticide
Toxicology, Second Edition
(R. Krieger, ed.), Academic Press,
pp. 799-843 (2001). Gold, L. S. et al. Drug Metab. Rev.
203-225 (1998). Ames, B. N. and Gold, L. S. Science
970-971 (1990). Ames, B. N., et al. Proc. Natl. Acad. Sci.
87: 7777-7781 (1990). Full text of all publications of the
Carcinogenic Potency Project are available at
- Chemicals are tested in rodents at near-toxic doses daily for
life, the Maximum Tolerated Dose (MTD).
- Species Extrapolation: Results in rodents are assumed to be
relevant to humans, and therefore an increase in tumors indicates a
potential human carcinogen.
- Dose Extrapolation: Tumor results in rodents at high dose (MTD)
are assumed to be relevant to human exposures even at very low
exposure levels, and the risk of cancer is proportional to the
exposure level, i.e. linear extrapolation.
N Positive )/ N Tested
|Chemicals tested in both rats and mice
|Chemicals tested in rats or mice
|Natural chemicals in roasted coffee
|FDA database of drug submissions
Natural chemicals are positive as often as
synthetic, industrial chemicals. More than 99% of the human intake
of chemicals is from naturally occurring chemicals.
Natural pesticides (the chemicals that plants
produce to defend themselves against predators and are present in
all the fruits and vegetables we eat) are as often positive as
- High dose effects that are not relevant to low human
- Carcinogenic processes in rodents that are not plausible in
- Bias in picking chemicals to test that were expected to be
positive. Our research indicates that bias is a minor factor for
several reasons, including:
- Chemicals were selected primarily because of extent of human
exposure, e.g. drugs, pesticides and workplace exposures.
- In 2 separate prediction exercises, expert scientists predicted
which of a set of chemicals that had not yet been tested would be
carcinogens when tested and which would not. The experts differed
from each other in their predictions. After the experiments were
done, the accuracy of the predictions in both exercises averaged
only slightly better than chance.
- The chronic, high dose rodent cancer tests is not adequate to
understanding human cancer risk at the low doses of most human
exposures. Tumor development in cancer tests is likely due, in
part, to high dose effects or processes that may not be relevant to
- No diet can be free of naturally occurring chemicals that cause
cancer in rodents at high doses. [See green chemical exposures in graphic on right].
- Emphasis on biological processes leading to tumors, using new
scientific methods to evaluate metabolism and effects of a chemical
- Qualitative Assessment: Compare key
steps in rodent tumor development to plausibility in humans, using
human physiology, metabolism, and epidemiology. If not plausible in
humans, then no risk to humans.
- Quantitative Assessment: If the process in
rodents is qualitatively plausible in humans then compare
quantitative factors between species, such as dose to the target
organ or quantitative differences in response to hormone
- If the process of tumor development in rodents is plausible in
humans or if evidence is not adequate to evaluate the process of
tumor development, then for regulatory policy a risk assessment is
- Current EPA Guidelines provide for two types of default
approaches to extrapolate from high dose rodent results to human
exposure — one linear and the other nonlinear. EPA
concluded, for example, that there is no cancer risk to humans from
chloroform unless exposure is high enough to cause cell killing and
cell proliferation; thus, there is a practical threshold in the
dose-response relationship. Human exposure to chloroform as a
by-product of disinfecting drinking water is far below that toxic
dose (see Graphic).
Chemicals That Do Not
- Formaldehyde: Damages DNA and
therefore is evaluated as relevant to humans. It is also a nasal
irritant when inhaled, and at high doses causes cell killing and
cell proliferation in both rodents and humans. Risk declines
markedly at doses that do not kill cells.
- Chloroform: The process of liver
and kidney tumor development in rodents is plausible in humans, and
requires high, toxic doses that kill cells. There is a threshold
dose below which there is no cancer risk to humans.
- Clofibrate, Gemfibrozil: Not
relevant to humans on quantitative basis. Peroxisome proliferation
occurs in both rodents and humans, but there is a genetic
difference — cell proliferation is seen only in rodents,
but not in mice with the human gene for the peroxisome receptor
alpha. Also, epidemiological studies of long-term use of these
drugs show no increase in human cancer.
- d-Limonene: Not relevant
to humans. The alpha2-urinary globulin protein is
specific only to male rats. Kidney tumors are induced by binding of
the epoxide of alpha 2-urinary protein to kidney cells leading to
toxicity and cell proliferation.
- Saccharin: Not relevant to
humans. Bladder tumors are induced only at high dose, and only in
rats. Tumor development is related to the physiology of the rat
urinary system, including formation of a precipitate, irritation
and cell killing.
[Participants in the new human relevance
paradigm include International Life Sciences Institute, Health
Canada, US EPA, International Programme on Chemical Safety]
Cohen, S. M., et al., Toxicol. Sci. 78: 181-186
(2004). Klaunig, J. E., et al., Crit. Rev. Toxicol. 33:
655-780 (2003). Meek, M. E., et al., Crit. Rev. Toxicol. 33:
Lois Swirsky Gold, Bruce N. Ames, Thomas H. Slone
This web page was supported by the Department of
Energy, Low Dose Radiation Research Program. From 1980-2008 the
Carcinogenic Potency Project has been supported by Department of
Energy (DOE); National Institute of Environmental Health Sciences
(NIEHS); National Toxicology Program (NTP); National Cancer
Institute (NCI); Environmental Protection Agency (EPA); University
of California, Berkeley, Dean’s Office of the College of
Letters and Science.
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