United States January 1980
Environmental Protection OPA 15/80
Agency
Toxic Substances
oEPA This Rat Died
In a Cancer Lab
To Save Lives
Animal tests find
most chemicals
aren't killers
Pick a chemical, any chemical. Feed it in whopping
quantities to rats, mice or both for a year or two. By
then, if they haven't already died, most will have cancer.
Right?
Wrong. Despite the popular belief that anything in suf-
ficient amounts will cause cancer in laboratory animals,
most compounds actually have been found innocent in
this regard. Indeed, of some 7,000 that have been tested
(some admittedly more adequately than others), all but
about 500 have gotten a clean bill of health.
A finding that about 7 percent of the compounds cause
cancer in animals does not exactly support those who
think "everything seems to cause cancer" or those who
would like to diminish our reliance on animal tests. That
would, in fact, be a grave error.
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As Dr. Marvin Schneiderman of the National
Cancer Institute puts it, "Some historical perspec-
tive may be in order here. During the 19th century
when germs were being discovered thick and fast,
much as carcinogens are today, the same sort of
skepticism prevailed as this or that microbe was
reported as the cause of one or another disease.
And there were the same kinds of arguments about
whether, in the face of scientific uncertainties, it
would pay to clean up the environment.
"Yet when the public water supplies of northern
Europe were, in fact, cleaned up — and remember
this was long before the advent of antibiotics —
epidemics of cholera and other gastrointestinal in-
fections virtually disappeared."
If popular or highly profitable substances are
found to be cancer culprits, of course, there is
bound to be strong resistance to the findings, and
researchers have not gone out of their way, as
some seem to think, to pick on them.
When saccharin began to come under increasing
suspicion, for example, some scientist thought or-
thotoluene sulphate, a frequent contaminant of the
artificial sweetener, might be the villain, rather
than saccharin itself. But it didn't work out that
way. Animals fed large amounts of saccharin-free
orthotoluene Sulphate developed cancer no more
often than similar, undosed control animals. Pure
saccharin, by contrast, produced an excess of blad-
der cancer in male animals, particularly when their
exposure to the sugar substitute began — via their
mothers' diet — during fetal life.
But doesn't sugar itself cause cancer in
laboratory animals if enough of it is given? Sure —
but only if it is injected under the skin, which is
not exactly how people ordinarily take sugar. That
is why animal tests for cancer have to be physiolog-
ically appropriate.
Bad News in a rush
As Dr. Schneiderman suggests, the testing of
chemicals for their cancer-causing potential is so re-
cent an enterprise that the bad news is bound to
come in a rush. There are now about 63,000 un-
tested compounds in commerce, with 700 to 1,000
new ones introduced each year. But as the backlog
diminishes and there is more pre-market testing,
the pace of discovery and unpleasant surprises is
likely to slow.
Meanwhile, there are two other reasons why
"everything seems to cause cancer" (neither of
Reprint from
The Washington Post "Outlook"
July 22, 1979
By Judith Randal
Science reporter in the Washington
bureau of the New York Daily News.
them traceable, as one wag has put it, "to the
failure of science to breed healthier laboratory
rats.")
One lies with the media process, which naturally
focuses on holes in the dike rather than reporting
how well the rest of the dike is doing. On a recent
Tuesday, for example, all three television networks
reported on their evening news shows that both
reserpine, a drug used in the treatment of high
blood pressure, and methapyrilene, an ingredient
of, among other things, many non-prescription
sleep-aids, had been found to be animal car-
cinogens. They did not report, of course, that
malathion, an insecticide dear to the hearts of
home gardeners, had at the same time come
through the test with its reputation for safety
unscathed.
The other reason stems from the fact that testing
chemicals for cancer in animals is enormously ex-
pensive. Typically, it costs $450,000 to $500,000
per compound, up from $150,000 to $200,000 as
recently as 1975 — and that only if rats and mice
serve as the test animals. If larger species more
closely related to man are enlisted, the price rises
substantially because it costs more to house and
feed them and they have longer life expectancies.
Given all this, it would be profligate to test
chemicals at random. Instead, it makes sense to
concentrate on compounds with suspicious molecu-
lar structures, such as the chlorinated hydrocarbon
family to which dozens of solvents, pesticides,
drugs, anesthetics and other products belong. It is
also wise to focus on those produced in large quan-
tities (although chemicals produced in less volume
to which certain groups of people are extensively
exposed are generally included, too.)
Even at that, educated guesswork is not always
correct. A study performed for the National
Cancer Institute by Litton Industries Bionetics
Laboratories of 120 common herbicides, pesticides
and fungicides is illustrative.
Each of the 120 compounds was fed to mice
from infancy through age 18 months in the largest
doses that would not quickly kill the animals
outright, and all of the 120 could have been ex-
pected to be carcinogens. Yet only 11 of them —
fewer than 10 per cent — resulted in a "significant"
number of tumors — more cancers than occur by
chance alone in treated animals than in undosed
controls.
The cumulative effect
Nonetheless, many people see no reason why
animal tests should have any relevance to humans
when such heavy doses of chemicals are used.
Again, the explanations are not as farfetched as is
popularly supposed.
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Following are the 26 chemicals or industrial processes identified by the International Agency for Research
on Cancer as associated with, or strongly suspected to be associated with, the occurrence of cancer in humans:
Aflatoxins
Aminobiphenyl
Arsenic compounds
Asbestos
Auramine (manufacture of)
Benzene
Benzidine
Bis(chloromethyl)ether
Cadmium-using industries
(possibly cadmium oxide)
Chloramphenicol
Chloromethyl methyl ether
Chromium (chromate-
producing industries)
Cyclophosphamide
Diethylstilbestrol
Hematite mining
Isopropy! oils
Melphalan
Mustard gas
2-Napthylamine
Nickel (nickel refining)
N,N-Bis(2 chloroethyl)-2-
Naphthy-lamine
Oxymetholone
Phenacetin
Phenytoin
Soots, tars and oils
Vinyl chloride
One is that people, unlike laboratory animals,
are exposed to more than one carcinogen in their
everyday lives and that — through the interactions
of body chemistry — exposure to a variety of car-
cinogens can be cumulative. In fact, some agents
"cooperate" to produce a greater harmful effect
than either can produce alone. Both smoking and
asbestos, for instance, can cause lung cancer in-
dependently. But the rate of lung cancer among
smokers who are also exposed to asbestos is higher
than mere double jeopardy would suggest.
Accordingly: 1) larger doses than man encounters
in the environment are justified in the laboratory
when the aim is to discover whether a particular
substance is capable of causing cancer at all and
2) no dose of a carcinogen, no matter how small,
can be relied on to be safe for every individual.
Contrary to what much of industry would have
people believe, the concept of a "threshold" or
"no effects" dose has no practical validity.
Worth bearing in mind, too, is that, because of
the costs, only a few animals — generally no more
than 100 — can be used to study any one com-
pound to which millions of people of varying sen-
sitivity are exposed. An example having nothing
directly to do with cancer may make the principle
clear.
When trials of swine flu vaccine were conducted
in 5,000 volunteers, there were no cases of
Guillain-Barre paralysis. But when 42 million peo-
ple later were inoculated, more than 200 became
paralyzed. By the same token, each animal in these
cancer experiments has to present just a fraction of
a person, making it essential to use large doses if
there is to be a prayer of detecting a compound's
relatively rare effects.
"Relatively rare," however, is a term to be used
with care. Even what scientists call a "weak" car-
cinogen can lead to many thousands of cancers if
hundreds of millions of people are exposed. And
the earlier the exposure begins and the longer it
continues the greater will be the risk, whether the
doses are large or small.
More fundamentally, it should be remembered
that although rats and mice are not little people,
they are like people in being collections of mam-
malian cells organized into tissues that undergo the
same biological processes. By giving large doses of
a chemical to a small creature with a rapid meta-
bolic rate, a short life span and comparatively few
cells, one can get a reasonable approximation of
what will happen in a larger creature whose meta-
bolic rate is slower and who has many times more
cells and a longer life expectancy.
Of the 26 chemicals from aflatoxins (by-products
of food molds), asbestos and benzene to vinyl
chloride gas (used in the manufacture of polyvinyl-
chloride plastics) that are proven causes of human
cancer, all — with the possible exception of
arsenic, which has yet to be thoroughly tested —
also cause cancer in animals. Is the reverse true?
The National Toxicology Program, for instance,
has so far completed tests of 194 compounds and
identified 92 of them as animal carcinogens and 19
as borderline — this because scientists could not be
95 per cent or more confident that their findings
were not just coincidence. Are all these compounds
also cancer risks for man?
While it would be nice to have a clear-cut
answer, that is currently impossible. An occasional
chemical such as DES (diethystilbestro!) produces a
type of cancer — in this case a cancer of the vagina
in young women — which otherwise is almost
unheard of and so enables scientists to track down
its source, (that proved to be DES use by expectant
mothers to prevent threatened abortion). But the
cancers that furnish such clues are few.
The more usual state of affairs is for a car-
cinogen to increase the rate of cancers that, for any
number of reasons, commonly occur anyway and
to take 10 to 30 years to do so besides. Thus it is
well nigh impossible to roll back the clock those
decades to trace an increase retrospectively to its
origins.
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Risk to humans
As if all of this weren't sufficiently complex, no
one knows how to determine from animal tests the
degree of risk to humans. For example, it was
found after the thalidomide tragedy that humans
are 60 times as sensitive to the baby-deforming
tranquilizer as mice, 100 times as sensitive as rats
and 700 times as sensitive as hamsters. But there is
now no way to reverse the order of such calcula-
tions so that quantitative risk assessments can be
made in advance. It simply has to be assumed for
the sake of prudence that humans are at least as
vulnerable to carcinogens as the rats and mice that
serve as their surrogates.
In fact, both the causes of cancer and the fre-
quency of certain kinds of cancer are subject to
shifts that probably reflect previous changes in
custom and technology. The widespread introduc-
tion of refrigeration and the consequent reduction
in food spoilage during the World War I era, for
instance, may well have been responsible for the
Bacteria, mammalian cells grown in glass-
ware and simple organisms like fruitflies that
can be inexpensively maintained in little space
are beginning to help science identify hazar-
dous substances in the environment.
When exposed to a carcinogen, they quickly
undergo changes in their genetic material that
can be observed and quantified. In the pres-
ence of a cancer-causing chemical, for in-
stance, unrepairable breaks may occur in the
chromosomes of mammalian cells. Or in the
case of bacteria, the introduction of such a
compound into their environment may render
their offspring no longer dependent on the
special nutritional requirements of their
parents.
To date, any one such test is thought to be
no more than 85 percent reliable. But cross-
checks can be made by running the tests in
batteries, and these batteries can pinpoint
chemicals that appear dangerous enough to
warrant full-blown testing in intact animals.
The beauty of these tests is that they can be
completed in hours, days or weeks rather than
years, and many can be performed for as lit-
tle as $2,000 each. In addition, they promise
to make it possible not only to tell if a sub-
stance is a carcinogen, but also if it can dam-
age the human fetus and the egg or sperm.
—Judith Randal
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decline in stomach cancer which began about 1930;
at least so the evidence suggests.
In the same way, there are those who think that
because cigarettes are not as strong as they used to
be, something similar may be in the offing where
lung cancer is concerned. If the scenario is correct,
there will not only be less lung cancer attributable
to cigarettes a decade or so down the road, but also
more caused by such other influences as air pollu-
tion and occupational exposure to carcinogens.
No matter. What can be said with confidence is
that animal tests have more often proved prophetic
than not. The vinyl chloride gas already mentioned
is a case in point. Granted, the tumors that were
produced by the gas in animals before it was
known to cause a rare form of liver cancer in
humans occurred in the symbal glands of hamsters,
facial structures that man does not have. Nonethe-
less, the premonitory evidence was there, confirm-
ing the principle that once a carcinogen circulates
in the bloodstream it is free to attack whatever
organ or organs may be most vulnerable.
Similarly, tests conducted on several species
beginning in the 1930s accurately predicted that the
chronic estrogen replacement therapy subsequently
prescribed for millions of women to ease them
through the menopause and retard the aging proc-
ess would significantly increase their risk of getting
uterine or breast cancer.
An equally dramatic example is provided by the
chlorinated hydrocarbon Kepone. It is a decade or
more too soon to know whether the employes of
the now-defunct Life Sciences plant in Hopewell,
Va., who were heavily exposed to this pesticide in
the course of its manufacture will have more than
their share of cancer, as rodent studies suggest. But
it should have come as no surprise that many of
them would be subject to tremors, other nervous
symptoms and sterility as a consequence of that ex-
perience. Experiments conducted on quail in 1964
resulted in exactly those injuries.
When it comes right down to it, then, animal
tests are meant to function as an early warning
system, and their biggest drawback is that people
fail to take them seriously. Given the fact that at
least 70 percent of cancer is thought to come from
exposures 10, 30 or even more years earlier, the
really pertinent question is what this is doing to our
future selves. With one in five Americans dying of
cancer, often prematurely, the public's scorn of
animal tests should be seen for what it is: playing
with fire.
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EPA is charged by Congress to protect the Nation's land, air and water
systems. Under a mandate of national environmental laws focused on air
and water quality, solid waste management and the control of toxic
substances, pesticides, noise and radiation, the Agency strives to formulate
and implement actions which lead to a compatible balance between human
activities and the ability of natural systems to support and nurture life.
If you have suggestions, questions
or requests for further information, they
may be directed to your nearest
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