The Linear No-Threshold Theory of Radiation
Carcinogenesis Should Be Rejected
Bernard L. Cohen, Ph.D.
Department of Physics & Astronomy,
University of Pittsburgh
Misconceptions About the
Causes of Cancer
Bruce N. Ames
Department of Cell and Molecular Biology, Lawrence Berkeley National
Laboratory, Berkeley, California 94720
Department of Molecular and Cell Biology,
University of California Berkeley, California 94720
Low-dose Irradiation Therapy Cures Gas Gangrene
Dr. Cuttler retired
from AECL (Atomic Energy of Canada) in July 2000, and is now President
of Cuttler & Associates Inc., providing consulting services. He served
on the Council of the Canadian Nuclear Society (CNS) for 10 years and
was its president in 1995/1996
It’s Time to Tell the Truth About the Health
Benefits of Low-Dose Radiation
Jim Muckerheide, the
State Nuclear Engineer for the state of Massachusetts, is a founder and
President of Radiation, Science, & Health, which is committed to
establishing a radiation policy based on science. He is also Co-director
of the Center for Nuclear Technology and Society at Worcester
Institute in Massachusetts.
to a Seminar Sponsored by the International Center for Scientific
May 10, 1993, at Paris, France
Is the Concept of a Linear
Relationship Between Dose and Effect Still a Valid Model for Assessing
Risks Related to Low Doses of Carcinogens?
The DDT Example.
William Hazeltine, Ph.D., B.C.E., Oroville, California, USA
It is gratifying to think that a Scientific Organization would want to
look at the old and new data on carcinogenicity of DDT, 20 years after
the United States Environmental Protection Agency (EPA) Administrator
announced that DDT was a carcinogen. The Administrator made this
decision and overturned his hearing Officer's findings concerning the
risks of allowing DDT's continued use in the United States.
You have to understand that I am an Entomologist-Ecologist by training,
who used DDT for crop protection, and for control of public health pests.
I tried to understand the details of risk from such use, because I was
the applicator on many occasions, and I was often exposed to higher
doses that most others in the area being treated. In addition, I have
continually practiced an approach to pest control which begins with a
threshold determination, to decide when and if control is necessary.
In many areas, this is called Integrated Pest Management. I began to
look at DDT in far greater detail in the early 1960s, when Rachel
Carson's book "Silent Spring" appeared, particularly because her
narratives were not consistent with my own experience. If I had been
mistaken, I wanted to be the first to know.
At the time, I was working on control methods for an aquatic midge in
Clear Lake, California, and Ms. Carson had told about the earlier
control efforts for this midge in Clear Lake, in infinite (and less than
accurate) detail. A few years later, I was listening to a founder of the
Environmental Defense Fund (EDF) who told our State Legislature that "anyone
who used or recommended the use of DDT did not know his business".
As part of the EDF presentation, which included an unequivocal statement
that DDT causes cancer, I obtained the book of photocopied papers which
the EDF witness had said were the “very zest of the Literature on DDT".
Thirty years later, I am still looking for convincing evidence to show
that I was wrong in allowing the use of this pesticide for food
production and health protection.
In the scientific field dealing with pesticides, there is a need for
more people to read the literature in detail, because often times, there
exists a temptation, even among scientists, to use "adversary science"
in place of objective science. There is also a tendency to rely on the
abstract or summary, in place of reading the whole article.
Adversary science is the art of telling only the facts which are
favorable to one's own belief, and hoping that the opposition (or the
media) will not be able to cite the data which was omitted. Right now,
the U.S. Supreme Court is trying to decide what acceptable scientific
evidence is. The problem has come into focus because we are allowing
lawyers and judges to replace the older and more appropriate method of
scientific debate. A real scientist will be the first to try to refute
his own hypothesis. Part of my commitment to look for the "facts" about
DDT, and having seen apparent abuses of scientific integrity', led me to
volunteer to help the lawyers for the U.S. Department of Agriculture and
the manufacturer of DDT in the U. S., when they examined the witnesses
from the Environmentalist's side, in the 6 month, long public hearing on
Cancellation of the uses of DDT.
As some EDF members had bragged, they would be happy to submit to "the
crucible of cross-examination." This was art excellent learning
experience, and it provided me with the exhibits and sworn transcripts
of the interesting parts of the proceedings. The issue of
carcinogenicity of DDT was one of the topics covered, and it is still
Separating the Issues
The specific topic of this seminar, "Is there a linear relationship
between dose (and time of exposure) and the development of cancers in
animals?" requires some ground rules, before the question can be
answered for the chemical DDT. These separate topics need consideration.
1. Is each isomer and metabolite considered separately or are all of
them considered as one chemical? The literature on testing seems to be
based both on, purified and "Technical" DDT, neither of which are
expected to contain much if any of the metabolite DDE. Good protocol
should specify the use of a purified single chemical of known molecular
2. Are the doses limited to those which do not damage the homeostasis of
the test animals? DDT is considered to be a relatively cumulative
chemical in vertebrate animals, and lipid residue data for all test
animals at sacrifice, correlated with presence and type of cancers could
be a better measure of dose response than constant feeding at given
doses in food or garage of neonatal animals.
3. With DDT, it is imperative to decide whether the dose-response data
should be consistent for all test animal species or hybrid classes, or
only for one or more kind or species of test animal, or for larger
taxonomic groups of test animals.
4. The time of exposure and the latent period before autopsy is
important, as well as the value of multi-generational studies.
5. Is the interest in the cancers only in the test animals, or is the
interest to provide predictions of risk for humans, or both?
6. Should tumors be counted as malignancies? As I read the Background
Statement for this Symposium, it seems clear that the discussion should
try to compare, or at least be aware of the conditions imposed in the
U.S. by the Delaney Clause (no cancers in any test animals under good
test conditions) as well as to the "no-effect dose level coupled with a
good safety factor" system for setting allowable residue tolerances in
raw agricultural commodities.
A corollary requires a consideration of whether or not there is a true "no-effect"
level for a carcinogen; this could involve use of epidemiological
considerations dealing with large areas and human or other animal
populations exposed to higher or lower doses of DDT for prolonged
periods of time. Extrapolation From Laboratory Animals to Humans During
the DDT hearing testimony of Dr Marvin Schneiderman, a statictician with
the National Cancer Institute, it suddenly occurred to me that DDT, as a
25 or 50% "Tracking Powder" was very effective in controlling mice and
bats, but it did not control cats.
I understood the difference to be that rat livers were like human livers
in their response to DDT, but mouse livers could essentially not be
induced with DDT. Dr. Schneiderman testified, as I recall, that the
protocol for laboratory cancer research required that two species of
test animals be used, and that both of these animals must not have a
known physiological system difference, if the data was to be used to
extrapolate the dose response information to humans.
The following exchange took place between Dr. Schneiderman and a lawyer
at the Public Hearing (Jan. 12, 1972, page 7142):
Question: If the purposes of these studies, Doctor, is to some day draw
some extrapolation to man, would you consider it a drawback that the
metabolism is different in mice and man? And if, as you, say, it has
been. demonstrated, then clearly one should not use an animal that
clearly has a different metabolism than man as an experimental animal?
Later in his testimony, Dr Schneiderman was asked if transplantation had
any relevance to carcinogenicity studies, because there was concern
about how to accurately determine: what was a cancer. His answer was:
“One of the criteria for malignancy is the transplantability of a tumor.
If a piece of tissue does not transplant and grow up into, another tumor,
it's assumed that it may not be malignant.”
Dr Schneiderman admitted that transplanting was not done in the
Bionetics study which he called a "minor defect" in that study. Between
mid February and November of 1972, I exchanged letters with Schneiderman.
The first references to species differences in liver inducibility were
(I) J.W, Gillett, 1970. in Biological Impact of Pesticides in the
Environment. Oregon State Univ., Corvallis Oregon, which deals with.
Japanese Quail and (2) Hart and Fonts, 1965. Arch. f. Exp. Path. and
Pharmak. 249:486-500, which considers sleep time chances with
barbiturates when test animals are dosed with DDT and other chlorinated
My last letter, which was not answered, included a copy of a paper by J.
R. Fonts, 1972 in Environmental Health Perspectives, October 1972,
55-66, that contains the following:
Thus, at doses and schedules of doses and at times after last dose of
the inducer that clearly established hepatic microsomal enzyme induction
by DDT or benzopyrene in rats and other species including monkeys, the
mouse did not show such induction or showed it only marginally. (references
omitted:, emphasis in text) This article gives some evidence for
variation in inducibility for rats and mice, but the differences in
tolerated DDT doses between mice and rats in the major papers usually
relied upon for determining carcinogenesis, clearly points to
physiological differences, with the mouse being aberrant, compared to
rats and humans in its response to DDT treatment.
This article also has a long list of references concerning inducibility.
A later paper by L. Tomatis et al., 1973 (lnt. J. Cancer 12: 1-20)
reports that tumors were found in Rat livers following doses of DDT. The
only reference to rats was a paper by Fitzhugh and Nelson, 1947 (J.
Pharm. & Exp. Therap. 89:19-30). No other organs besides the liver were
involved, and only tumors were found, according to Tomatis.
In 1986, EPA published 'Guidelines for Carcinogen Risk Assessment'.
(1986 vol 51, of the O.S. Federal Register, pages 33.992-34003 and
reprinted in EPA/ 625/3-90/017, Sept. 1989). Some of the pertinent
“The strength of the evidence supporting a potential human
carcinogenicity judgment is developed in a weight-of-evidence
stratification scheme. (p33994)” The weight of evidence that an agent is
potentially carcinogenic for humans increases:
(3) with the occurrence of clear-cut dose response relationships as well
as a high level statistical significance of the increased tumor
incidence in treated compared to control groups;
(4) when there is a dose-related shortening of the time-to-tumor
occurrence or time to death with. tumor; and
(5) when there is a dose-related increase in the proportion of tumors
that are malignant. (p33 995) ---
A statistically significant excess of tumors of all types in the
aggregate, in the absence of a statistically significant increase of any
individual tumor type, should be regarded as minimal evidence of
carcinogenic action, unless there are persuasive reasons to the contrary
(p33995). In the absence of appropriate human studies, data from species
that respond most like humans should be used, if information to this
effect exists. (p33997).
Major Studies The "Bionetics" Study (Innes et al. 1969. J Nat. Cancer
Ins t 42:1101-14) was an ambitious project which was intended to screen
120 chemicals on mice at doses which were close to that which would
cause toxic symptoms. For DDT, the dose was 46.4 mg/Kg, by stomach tube
from day 7 through day 28 of age, and the dose in the food was then 140
ppm for the remainder of an 18 month test period. The mice used were two
essentially new crosses, using two different male stocks and the same
mother stock for both crosses.
The test began with 18 mice of each gender and of each cross (72 mice
per chemical). All mice tested for each chemical were given the same
dose of chemical, apparently for the purpose of answering only the
single question of could the administered chemical induce tumors or
Dr. Falk, one the Co-authors of the lnnes et al. paper presented a
speech, which, was later printed as an article (Nat'l. Pest Control
Operators News, October 1971 p4-6 and 29-31). In this presentation, Dr
Falk provided comments about the test methods and the implications of
the test results. He also commented about the way the test mice were
bred and the fact that the suitability of these crosses for cancer
testing was unknown. There apparently was no history of cancer
susceptibility of these crosses.
Dr Falk told about various parts of the test, then he said: “We came up
with positive results, for instance, a significant number of Hepatomas
in mice on 140 ppm DDT in the diet. But as we decrease the DDT level to
that which we [humans] are exposed to now, most likely we would have to
conclude that the hepatoma incidence would be 0 %.”(emphasis added) One
paragraph of the Falk article is long but important to our understanding.
It says, referring to the Bionetics Study:
“The lack of malignancy on the liver and lung tumors produced a
controversy which while quite artificial was, nevertheless, quite heated.
The Delaney amendment compels the Food and Drug Administration to ban
any chemical for use on -or in- food if it can produce cancer at any
dose level and by any mode of administration. It specifically states
that the tumor has to be a cancer. So the question arose, did these
tumors have a tendency, to become cancers?
Three types of tumors were observed in these studies. They were either
hepatomas, and by definition a hepatom is a benign, tumor, i.e. it does
not invade surrounding tissue or metastasize to other organs, in other
words it grows confined to the organ of origin. With time the tumor may
become invasive, in which case its cells attack the surrounding tissues,
but it may as yet not spread to distant tissue like lung or lymph nodes.
At that stage, it would be malignant.
This behavior is quite characteristic for mouse tumors. They do not
quite behave like human cancers. Whereas a hepatoma is a benign tumor,
it is generally conceded that given another six months, it would most
likely have become malignant and killed its host. But you can appreciate
that the FDA has a difficult decision to make because at the moment of
sacrifice at 18 months, most of the tumors were benign.
Lung tumors, the second type of tumors, similarly were benign tumors
which probably would have turned malignant with time. The only neoplasm
that was recognized as a malignant tumor was the reticulum cell sarcoma
(a type of lymphoid tumor.) (Emphasis added) The data published for the
Bionetics Study (Innes et al., cited above) shows "lymphomas" as
occurring at a 0.05 confidence level for all mice tested, with females
of each hybrid type having "lymphomas" at the 0.01 confidence level.
These levels of confidence do not suggest clear and convincing evidence
of carcinogenicity, unless one wants to enter into the speculation or "educated
guess" type of logic which Dr Falk referred to.
Dr Falk then goes on to explain that if the tests were allowed to go to
2 years, there would have been natural mortality, with cannibalism or
decay "when no one was looking." In early 1974, following the
cancellation, in the U.S. of most uses of DDT about 2 years earlier, an
Appropriations Subcommittee of the U.S. Congress asked EPA "To Initiate
a Complete and Thorough Review Based on Scientific Evidence of the
Decision Banning The Use of DDT".
Testimony by' Leonard Axelrod, Ph.D., the EPA person who was doing the
review is recorded in the transcript of hearing for April 4, 1974. It
reads in part:
“There is at the present time, no evidence that DDT is carcinogenic (or
tumorogenic) in any animal species when administered at levels less than
two orders of magnitude higher than the maximum dose attainable by plant
manufacturers and workers over a lifetime of exposure.”
6. There is at present no evidence from experimentation that DDT is
either teratogenic or mutagenic.
7. There is no evidence from human monitoring studies over a 5-year
period that DDT as occurring in the environment has caused an increase
of any known physiological dyscrasia. A copy of a later draft of this
Report, dated June 5, 19741 was obtained from a student who was allowed
to work at EPA in Washington, D.C. during the time this study was in
In the part dealing with "Carcinogenesis and Tumoragenesis" (pp 21-22),
Dr Axelrod lists the published reports available since January 1972
which he had thoroughly reviewed. The list and conclusions with Dr.
Axelrod's hand written corrections, suggest a reasonable review of the
pertinent literature available at that time. Discussion and evaluation
of the papers used by the environmental "experts" in the record of the
public hearing are included by reference by Dr. Axelrod, in this draft.
One of the conclusions in the 6/5/74 draft appears to be based on the
studies referred to as the Lyon and the Hilan Studies (Turusov et
ai.1973 (J. Nat'l. Cancer Inst. 11:983-97) and Terracini et ai.1973 (Int'l.
J. Cancer 11:747-64) respectively. It is important enough to be quoted
here: “If all tumors were considered carcinomas then an extrapolation on
a linear-dose-response basis would correspond to one or two additional
cases of liver cancer in 200 million humans” --- If mice have a
predictive value for human risk of cancers, which appears to be in
serious disagreement with the EPA Guidelines (Protocols?), this data
would suggest a 1 to 100 to 1 to 200 million added risk value, or 100 to
200 times what our EPA has proposed as a de minims cancer risk level for
residues of pesticides in food, The conclusion of Dr Axelrod in June of
1974 was changed in December 2, 1974 Working Paper. In it he says: “One
can conclude that available evidence indicates that the likelihood that
DDT is a human carcinogen is very low.”
Note: Dr Axelrod died suddenly, shortly after the preparation of the
12/2/74 draft. The final Report by EPA is dated July 1975, and it does
not read anything like the Axelrod writings. The final Report appears to
have been sanitized, possibly to sustain the EPA Administrator's earlier
conclusion that DDT was carcinogenic. Dr. Samuel Epstein, a witness
called by the EPA and the EDF at the Public Hearings on January 14, 1972
has a different perspective of human risk than Dr. Axelrod.
Epstein testified, on page 7370:
Q.: Based on your experience and upon your survey and analysis of the
literature, would you give us your professional opinion, if you have one,
either the presence of DDT in the human environment represents a
significant carcinogenic hazard to man?
A. “I can only answer that qualitatively, and the answer is yes,”.
Q. In your professional opinion, can a man be safely exposed to any
level of DDT? The answer is no. During his: testimony, Dr. Epstein who
said he was on several advisory committees to the group which, produced
the document known as "the Mrak Report", introduced 4 pages of a paper
referred to as 'the unpublished Fitzhugh Report,' which Dr. Epstein
characterized as one of only 4 studies up to that time, "which provide
definitive evidence of carcinogeniclty."
This manuscript (O.G, Fitzhugh et al. undated, titled "A Summary of a
Carcinogenic Study of DDT in Mice-- Unpublished data from the Bureau of
Science, Food and Drug Administration), along with 2 attached memoranda
(dated 1/30/69 and 9/15169) were only made available after this witness
was excused, and no longer available for testimony . The total document
shows some possible reasons why this study was not published, and does
not invoke a reeling of confidence in the predictive value of this study.
Page 33 of Attachment number 2 contains information, to show: Unusually
high mortality in some male mice during the second year of the 2 year
study resulting in relatively few animals at risk when they were most
likely to exhibit tumors. Report of a tumor of the testis in a female
mouse. Report of an ovarian tumor in an animal reported lost from the
animal quarters earlier. A problem with the DDT dose occurred in the
67th week, where the 100 PPM dose was increased to 300 PPM, resulting in
increased mortality. (page 4 of Attachment 2, dated September 15., 1969)
Note: The Report shows 318 of 100 male, and 22 of 100 female mice died
between weeks 62 and 66. The unpublished Fitzhugh Study used only one
dose of DDT, so no dose-response information can be drawn from it.
Dr. Epstein characterizes the results on the research reported by Hayes
et al. 1971(Arch, Env. Health 22:1-9), Laws et al. 1967 (Arch. Env.
Health 15:766, and Laws, 1971 (Manuscript submitted to EPA May 13, 1970)
as "inappropriate", yet the first two of these papers report on work
done in humans, and the third showed' apparent inhibition of the "take"
of transplanted cancer cells in mice, when the mice had been treated
with DDT. (see discussion under Benefits)
There are tests reported where DDT was administered to dogs (Lehman,
1952. Q. Bull. Assoc. F&D Officials of US.16:7, and later Ottoboni 1977
(Arch. Environm. Cont. & Tox. 6:8-101), llansters (Agthe et al. 1970,
Proc. Soc, Exp. Biol. & Med. 134:113) and Rhesus Monkeys (Durham et al.
1963, (Arch. Int. Pharmacodyn. 141:111).
All of these tests, except for Ottoboni's work are questionable because
of the conditions of the tests. Ottoboni tested purebred Beagle dogs
continuously dosed for 3 generations at 10 ppm DDT in their feed, with
sacrifice at age 2 I/3 years. No adverse effects due to the treatment
were found: She reported (personal communication): that there were
observable beneficial effects in the treated dogs in this
multigenerational study; she also said that the technicians began to
refer to the untreated control dogs as "the DDT deficient animals."
Appended to this paper is a copy of some tables presented by Carrol Well
who was with the Mellon Institute in Pittsburg, Pennsylvania. These
tables were part of a presentation to the Entomological Society of
America annual meeting in. 1975, to show some of the problems associated
with trying to interpret the kind of data that can come from animal
assays for carcinogenicity in mice. In the Table marked "A", if by
chance the male group number 5 had been the control group, all the other
untreated groups would have been called positive. "B" shows the
potential effect of diet type and; "C" shows the difference in tumors
when mice are allowed to eat all they want, compared to some limitation
on the amount of food they receive.
The study reported by R. Kimbrough et al., 1964 (J Nat'l. Cancer Inst.,
33:215-25) confirms that Rats also can show adverse effects (leukemia)
due to use of a purified diet, and not due to the DDT used in their
tests. Conclusions About Cancer Studies The most reasonable conclusion I
can draw, based on the review of the references I have looked at and the
other materials available to me concerning DDT and cancers in test
animals, is that there is not enough data to get any kind of clear
picture about dose/response for cancers with DDT in mice, if such a
Furthermore, there will probably be few if any new studies because DDT
is essentially gone from the market-place in the U.S., which is the
source of most of the funding for massive cancer research programs. If
one accepts the idea that mouse livers are essentially non-inducible
with DDT, then there seems to be two alternative and perhaps connected
hypotheses to work with. One is that the mouse studies are really
looking at animals whose physiological systems are overwhelmed by a
foreign chemical and that adverse results occur because of this
disruption of homeostasis in the test animals, and not due to a site or
system specific carcinogen.
The second hypothesis is that there is no dose/response correlation for
cancers or hepatomas, when DDT is administered. Both of these hypotheses
neglect the question of whether or not DDT is carcinogenic in the
animals tested so far, and the most reasonable answer to this question
is that the evidence available to date does not support the idea that
DDT is a carcinogen.
Two studies with humans have been reported, and both are negative for
definitive adverse effects. These were the studies which Dr. Epstein
dismissed as inappropriate. Hayes et al, 1971 (cited earlier) fed DDT
volunteers doses of DDT at rates of up to 35 mg. per day for 21.5 months,
and some of the people were observed for 5 years from the initial
feeding period. The dose was calculated at 535 times the average daily
intake in the U.S., and no adverse effects were observed.
Laws et al. 1967, (cited earlier) followed 35 men with 11 to 19 years of
high exposure at a facility where DDT was manufactured, and these men
showed no adverse effects attributed to exposure to DDT. Based on
storage and excretion levels, the average daily intake was estimated at
3 to 18 mg per man per day.
This compared to .04 mg per day for the general population. Fat residues
for these workers was 39 to 128 times the level in the general
population. Even though the evidence is negative, it seems to be of more
value in assessing the risks of DDT exposure to humans than all of the
mouse data accumulated over the years. Even with the use of DDT
beginning with World War II, and extending up to 1972, any evidence of
increased human liver cancer rates appears to be absent. This may be
analogous to a hypothetical cancer researcher saying "We must study
reality to see if it works out in theory.
" Beneficial Effects of DDT in Animal Tests
It is interesting to look at the tests which do not cause some harm, but
rather show some measurable results which seem to be beneficial to the
test animals. Once in a while, there may be a surprise and the expected
results may not occur. We all need to be open to letting the data tell
us what it has to say.
M. A. Ottoboni, 1984 ('The dose makes the poison', Vincente Books,
Berkeley, California, 222 pp.) provides: an understandable discussion of
the types of chemical carcinogens. The list of types include:
Primary Carcinogens - They directly start the cancer process. (example-Radiomimetic
Procarcinogens - Not carcinogenic, but may be converted to a carcinogen
Cocarcinogens (=promoters) - Enhance the carcinogenic action of another
chemical. They may change the rate of metabolism of carcinogens, alter
biochemical pathways or interfere with the repair mechanisms that would
otherwise reduce the effect of the carcinogen.
Secondary Carcinogens - Not carcinogens, but they indirectly cause
tissue damage. (example-Oxalic acid may produce bladder stones which,
over time can irritate the bladder and cause cancer from the irritation)
She also points out that chemical carcinogens are dose related and quite
site specific. Furthermore, low doses and high or "heroic" doses may not
act the same way on test animals. She says at page 1 the use of heroic
doses is accepted without question by regulatory agencies despite its
acknowledged pitfalls, while the public is generally unaware that such
The pitfalls derive from the fact that the biochemical fate of very
small doses of a chemical is usually not the same as that for large
doses. The differences that chemicals display between their acute and
chronic toxicities is testimony to the fact. Small doses of a chemical
may follow metabolic pathways that does not convert it into a carcinogen,
but with increasing doses the pathway becomes saturated and the excess
chemical is diverted to a new pathway that does convert it to a
carcinogen. Or, small doses of the chemical may be prevented from
exerting carcinogenic activity by combination with a biochemical
normally present in the body.
If the supply of the biochemical is expended by the large doses, the
excess chemical is then free to exert its carcinogenic effect. In
considering the beneficial effects, such as the apparent prevention of
cancers, there may be a whole group of physiological activities working
in concert. There are some studies which I want to call to your
attention, particularly because they seem to refute the idea that DDT in
test animals will result in adverse effects.
K.C. Salinskas and A.B. Okey, 1975 (J. Nat, Cancer Inst.55:653-57)
predosed Sprague-Dawley Rats with diets containing either 100 ppm of DDT
and or 250 ppm of Malathion, for 14 days. Beginning on day 50 following
the conditioning, these rats were dosed; daily by stomach tube for 21
consecutive days with 0.714 rag. of dimeythylbenzanthracene (DMBA), a
known carcinogen. These animals were sacrificed 23 days following the
start of the DMBA treatment. The DDT treatment reduced the incidence of
rats with leukemia and mammary tumors, and no deaths occurred with the
DDT treated rats until the time of autopsy.
The significance of the absence of tumors in rats treated with DDT was
greater than .001. The authors speculate that the DDT caused increase
hepatic enzyme activity, causing increased metabolism and excretion of
E.M. Walker et ai.1970 (Indust. Med. 39(7):60) administered DDT in
dimethyl sulfoxide (DMSO) 4 to 6 days l.P. to mice which had Ehrlich
ascites carcinomas. The note I saw was short, and the reason for
mentioning this reported inhibition of tumor development was to comment
on the use of DMSO as a carrier. The same solvent was used with DDT in
part of the Bionetics Study, which was looking for, but not finding
evidence of Teratogenicity in mice when DDT in DMSO was administered
When I received the document which contained the report of this study, I
wrote to the National Institute of Health and asked about this use of
DMSO. The NIH response was that DMSO alone was tolerated without
teratogenesis in the types of mice under test. The concern I have is
that in those pesticides where there was some reported adverse effects,
the coupling effect of DMSO could cause greater than simple additive
effect. In live animal tests, the cell walls might be crossed faster
with a solvent such as DMSO, because of its alleged capacity to
penetrate cells and its solvent which could cart another dissolved
chemical through cell walls, that otherwise might not have been crossed
by the chemical without the use of the solvent.
Using a test where cancer was induced in mice by subdural implantation
of methyl-cholanthrene crystals, E.R. Laws (in a manuscript submitted to
EPA on May 13, I1970), reported that cells from this cancer could be
transplanted by injection of a saline suspension of cells into other
mice. He reported that visual tumors developed in I0 to 18 days, with
subsequent relentless growth and eventual death of the mice as the real
DDT administered at 5.5 mg/kg/day gave preliminary evidence of
prolonging the life of the treated and challenged animals. There was
some suggestion that DDT had an adverse effect on the Soi Potassium
stimulated phase the two, and an alternative suggestion was that DDT
might have a "general subliminal toxic effect on the whole animal which
could make it a less suitable host for the transplanted tumor.
A paper by R.P.H. Thompson et al.,1969. (Lancet II (7161):4-6, July 5,
1969) explains how DDT was administered to a 17 year old boy for control
of unconjugated juvenile jaundice. This treatment replaced
phenobarbitone which had been used earlier. The mechanism suggested for
the successful therapy was the induction of liver microsomal enzymes,
which resulted in educed plasma bilirubin levels.
The treatment resulted in, producing an elevated plasma DDT level, and
for 7 months after the end of DDT therapy, the bilirubin level had
remained low. The authors reported no side effects were noticed, there
was no proteinuria, and other liver function tests and routine
haematological tests remained normal. A paper by Hazeltine in 1971 (Clinical
Toxicol. 4:55-61), looked at the literature for evidence about DDT
residues in people living in agricultural areas, and the possible impact
this chemical and other agricultural chemicals might have on juvenile
The conclusions I drew were that DDT appeared to: be present in
significant (therapeutic) levels in the body fat of people living in
this area that the observed infants who were breast fed and had a
reduced incidence of jaundice, could be explained by the effects of this
residue. There were other interesting parts to this literature review,
such as the competitive or counteracting effect on liver enzyme
induction by DDT, attributed to exposure to the pesticide Malathion.
The competitive or antidotal effect of DDT and barbiturates was the
basis for hospital emergency room treatment of attempted barbiturate
suicide cases with injected DDT. Richard Rappolt Sr.,MD. personal
communication) Dr. Rappolt treated at least two patients with DDT
dissolved in peanut oil; both patients were reported ambulatory and went
home the next day. This therapy evolved from the understanding of
veterinary, practitioners who use barbiturates to antidote animals that
have organochlorine pesticide poisoning.
Apparently the competitive antidotal action explains the speed of effect,
which is too fast for enzyme induction and metabolism of the excess
chemical. It was also interesting and sad to see Dr. Rappolt dismissed
from the hospital emergency room where he practiced for reasons that
appeared political. The published newspaper story explained that he was
dismissed for experimenting on people with DDT; his reply was that a
good emergency room physician must be ready for all kinds of unusual
Finally, while not directly dealing with cancer testing, but still
bearing on the rat liver enzyme induction issue, two papers should be
mentioned. These are P.R. Datta 1970, and Datta and Nelson, 1970
(Industrial Med. 39:190-94 and 195-98). These papers report on a study
in which carbon |4 DDT and its metabolites were applied to perfused rat
liver and kidney slices, with the rate and metabolite production
recorded. The experiment was well quantified by accounting for the total
Each step of the metabolic process was confirmed by synthesizing the
molecules and applying each one to confirm, the entire process. Keep in
mind that this was an in-vitro study and there was no fat sink to
preferentially absorb (selectively partition) the highly lipid soluble
molecules, as would occur in a living rat. These workers showed that the
metabolism proceeded from DDT to DDA, a water soluble metabolic product.
The rats used in this test were preconditioned with DDT for three days
prior to the use of their tissues. These authors reported that the first
roughly two-thirds of the metabolism occurred; in the liver, and the
last third in the kidney. The rates of metabolism were found to be quite
rapid in this isolated tissue system.
The alleged persistent DDT metabolite in nature (DDE) was degraded to
DDA, with 14.5% of the DDE converted to DDA in 24 hours in untreated,
unconditioned animals, and 23.8% found as DDA after 12 hours in rats
which had been conditioned for 3 days with DDT.
In response to the format proposed for this Seminar, and looking for
significant correlations between forecasts and the facts available today,
it appears that the suggestions and predictions made in the 1970s about
DDT as a human carcinogen were only strawmen which have failed to occur.
The data from a number of studies showing some alleged adverse effects
in mice fed at maximum tolerated doses of DDT for lifetimes (more or
less) is suggestive but extremely difficult to interpret.
At the same time, there is evidence to refute the hypothesis that DDT is
a human carcinogen. These conflicts appear to occur for a number of
reasons. Some of these reasons are:
1. The choice of inappropriate test species and protocols to evaluate
DDT as a carcinogen, has led to a diversity of conflicting results, high
doses of DDT have seemed to produce random physiological effects, but
these conflicting data have had the tendency of making the whole process
of dose-response evaluations of the data for cancers remote, if not
2. There is no clear data for the doses correlated with cancer
production in mice treated with large doses of DDT, in the literature
have reviewed for this seminar. This suggests that DDT is not causally
related to the adverse conditions seen in the test mice, so other
explanations should be sought to explain the abnormal pathology which is
3. People who work in "pure research" do not seem to be interested in
getting into the political arena, where their research findings may be
expected to be made to fit into some social framework, or to support
4. Extrapolations of data that may provide some meaningful insights may
also involve some risk of being wrong. Therefore such extrapolations are
usually avoided by "pure research" workers, and let to the “apocalyptic",
who do not seem to care much about accuracy or integrity.
5. Positive data on anticarcinogenic and therapeutic effects of are
generally neglected, when looking at dose-response data. Most
researchers are looking for harmful effects. Society does not reward
findings of no harm.
6. Tere is a strong tendency to neglect the unprovable such as the
evidence on improved vigor and increased life span for the human
population, which has been exposed to low levels of DDT for many years.
7. We need to examine the idea that a potential or weak organic chemical
carcinogen, can also act in a way analogous to a therapeutic agent at
non-carcinogenic doses, to show beneficial actions within a
dose-response relationship. If there are both beneficial effects and low
dose, and harmful effects such as carcinogenicity at high dose, from the
same chemical molecule than it could be appropriate to label a
carcinogen as beneficial. Selenium, the inorganic element may to provide
a model for this kind of thinking.
8. In any carcinogenic testing experiment, the most important question
concerns what is the highest dose which the test animal can tolerate
without loss of normal physiological body system functions. Doses which
cause loss of homoeostasis are not expected to show reproducible
dose-response effects at any particular target site. This high dose loss
of homeostasis is the most reasonable way to interpret the alleged DDT
mouse cancer test data reviewed for this report.
1. B.L. Cohen, Critical Rev. in Environ. Control. 22:243-364; 1992.
2. B.L. Cohen, Int. Jour. of Epidemiol. 19:680-684; 1990.
3. H. Morgenstern, Am. J. Pub. Hlth. 72:1336-1344; 1983.
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6. B.L. Cohen, Int. Jour. of Epidemiol.
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8. BEIR (National Acad. of Sciences Com. on Biological Effects of
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