Arch Toxicol (2011) 85:1495–1498

DOI 10.1007/s00204-011-0728-8

REVIEW ARTICLE

Muller’s Nobel lecture on dose–response for ionizing radiation:

Received: 13 April 2011 / Accepted: 14 June 2011 / Published online: 30 June 2011
Ó Springer-Verlag 2011

Abstract In his Nobel Prize Lecture of December 12, may provide (Carlson 1981). As a direct offshoot of this
1946, Hermann J. Muller argued that the dose–response for concern, follow-up research in Muller’s laboratory assess-
radiation-induced germ cell mutations was linear and that ing the nature of the dose–response for radiation-induced
there was ‘‘no escape from the conclusion that there is no germ cell mutations supported a linear interpretation
threshold’’. However, assessment of correspondence thereby suggesting that there was no safe dose no matter
between Muller and Curt Stern 1 month prior to his Nobel how low or apparently inconsequential (Calabrese 2009,
Prize Lecture reveals that Muller knew the results and 2011). This was a theme that motivated the remainder of
implications of a recently completed study at the Univer- Muller’s professional life. This motivation would be
sity of Rochester under the direction of Stern, which transformed into passion as the world entered its atomic
directly contradicted his Nobel Prize Lecture. This finding phase with the dropping of the atomic bombs and the start
is of historical importance since Muller’s Nobel Lecture of atmospheric testing of such weapons. In fact, with his
gained considerable international attention and is a turning Nobel Prize in hand and coupled with a commitment to
point in the acceptance of the linearity model in risk educate societal leaders to the long-term dangers of
assessment for germ cell mutations and carcinogens. atmospheric fallout for the human genome, Muller would
be a force to contend with. In the end, it would be largely
Keywords Linearity
Threshold
Hermann J. Muller
due to Muller’s knowledge, leadership, message, perse-
Nobel Prize
Risk assessment
X-rays
Ionizing radiation verance, and passion that governments and society would
change the way they viewed the risks of low doses of
ionizing radiation (Carlson 1981). This leadership was
In 1927, Hermann J. Muller demonstrated that X-rays evident in the 1956 recommendations of the US National
caused mutations in male fruit fly germ cells (Muller Academy of Sciences (NAS) BEAR (Biological Effects of
1927). Nineteen years later, he would be awarded the Atomic Radiation) I Committee, of which Muller was a
Nobel Prize for this finding. Muller took his discovery member, that lead to governments changing how they
seriously, trying to determine not just what it meant sci- evaluated the risks of germ cell mutation, regulating ion-
entifically but for society as well. In fact, soon after his izing radiation as if there was no safe dose, using the linear
discovery, he expressed strong concerns about the indis- dose–response model. Prior to the BEAR I Committee’s
criminate use of X-rays, challenging the medical commu- recommendation, Muller and his geneticist colleagues were
nity to be aware of the benefits and dangers that X-rays seen as bothersome governmental-medical critics; yet, with
this public and transforming recommendation, they became
in effect, now part of the system and its intellectual lead-
ership. Within a year of the BEAR I report, the first efforts
E. J. Calabrese (&) to regulate radiation-induced cancer risks were also
Environmental Health Sciences, Department of Public Health,
placed within a linear context by the National Committee
School of Public Health and Health Sciences, University
of Massachusetts, Amherst, MA 01003, USA for Radiation Protection (NCRP). Within a few years,
e-mail: edwardc@[Link] the linearity paradigm had transformed governmental

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regulatory agencies in many countries, including recom- that the ‘‘very low dose’’ tested was still some many
mendations of the UN. Furthermore, some 20 years after thousand fold greater than human background exposures to
geneticists took control of the ionizing radiation risk ionizing radiation. However, of greatest concern was
assessment issue, the next generation of geneticists and Muller’s failure to temper his Nobel Prize Lecture remarks
their chemical toxicologist peers, acting through the first in light of the fact that he had recently become aware of a
NAS Safe Drinking Water Committee in 1977, followed large experiment conducted at the University of Rochester
the lead of the BEAR I Committee and applied linearity to by Ernst Caspari and Curt Stern (American Philosophical
cancer risk assessment for chemicals (National Academy Society—E. Caspari File 1946/1947b), which failed to
of Sciences 1977). In retrospect, the transformation of a support linearity. This study had heightened importance
threshold guided risk assessment to one now centered on a because it was testing the effects of ionizing radiation at
linear dose–response started and reached completion with the lowest dose rate then ever tested (2.5 r/day). These
Muller (1890–1967), although he did not live long enough findings supported a threshold interpretation and chal-
to see how most public health oriented and regulatory lenged Muller’s striking ‘‘no excuse’’ statement (American
agencies worldwide dealing with radiation and chemical Philosophical Society—H. J. Muller File 1946/1947a). In
exposures had responded to his concerns and adopted his fact, these experiments were conducted with a special
message (Bolt et al. 2009; Calabrese and Baldwin 2003; strain of fruit flies that Muller had supplied to Stern. Muller
Hoffmann 2009). was also a formal consultant to the project, given special
While Muller received innumerable accolades for his clearance by the US government. The study was completed
achievements and leadership, recently unearthed corre- by August of 1946, a little more than 3 months prior to his
spondence between Muller and Stern (American Philo- Nobel Prize lecture. The following represents a series of
sophical Society—H. J. Muller File 1946/1947a) challenge letter exchanges between Stern and Muller concerning the
the veracity of Muller’s strikingly unequivocal statement Caspari and Stern manuscript (American Philosophical
concerning the effects of ionizing radiation on germ cells in Society—H. J. Muller file 1946/1947a):
his Nobel Prize Lecture. His presentation was a galvanizing
September 24, 1946: Stern to Muller: ‘‘Dr. Caspari’s
moment in the debate over the shape of the dose–response
report on his work is now being typed and I wonder
in the low-dose zone for ionizing radiation. During that
whether we could bother you with sending you a copy for
memorable occasion, he stated that there could no longer
your new comments.’’
be any doubt that the dose–response for ionizing radiation-
induced germ cell mutation was linear. He then cited the September 27, 1946: Muller to Stern: ‘‘Also, I’d be
work of several people (e.g., Oliver 1930; Hanson and glad to see Caspari’s paper too.’’
Heys 1932; Timofeeff-Ressovsky et al. 1935) that linearity
November 6, 1946: Stern to Muller: ‘‘Caspari’s manu-
best described how radiation affected germ cells (i.e., fruit
script has finally been typed and we would appreciate very
fly sperm). In this acknowledgment, he failed to qualify it
much your critical reading of it.’’
by noting that the doses used were extraordinarily high,
having no obvious relevance to the human condition. He November 12, 1946: Muller to Stern: ‘‘I have just
also neglected to acknowledge other contemporary sub- arrived from an absence of over 2 weeks and find the Caspari
stantial findings that did not support a linear dose–response manuscript here waiting for me. Unfortunately, it catches me
(e.g., Hanson and Heys 1929; Weinstein 1928; Stadler again when I am in a tremendous pressure of work, trying to
1930; Serebrovsky and Dubinin 1930; Calabrese 2009). He make up both the trip just passed and for another one to come
then claimed that if that was not enough then there could be in a few weeks. However, I see that it is very important and
‘‘no escape from the conclusion that there is no threshold’’ shall do all I can to go through it in a reasonable time, surely
based on the research of his graduate student protégé, Ray- before I leave again early in December. I hope that Caspari
Chaudhuri. However, Muller did not mention that there can wait that long if necessary. In the meantime I wonder
were several concerns among his peers with these data, whether you are having any steps taken to have the question
including confusion over the appropriateness of his control tested again, with variations in technique. It is of such par-
group, substantial variability [see Caspari–Stern Corre- amount importance, and the results seem so diametrically
spondence, November 7, 1947 (American Philosophical opposed to those which you and the others have obtained,
Society—E. Caspari File 1946/1947b)], inadequate that I should think funds would be fourth coming for a test of
reporting of research methods, small sample size, lack of the matter. It is not, of course, that I doubt Caspari’s reli-
data on quality control parameters, known problems with ability at all, but only that I naturally share the same doubts
temperature control, lack of data on lethal clusters, sterility/ which he himself expressed. Of course, I am only judging by
fecundity, sex ratios, selection criteria for males, that he the summary and a quick glance through the paper, and have
changed the fruit fly strain in the middle of the study and not had the opportunity to read the details.’’

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Thus, it is clear that Muller knew of the significant present assessment of Muller’s Nobel Prize Lecture sug-
challenge to a linearity dose–response interpretation by the gests that Muller was deceptive in his presentation, thus
Caspari and Stern manuscript, and he knew this in the profoundly enhancing acceptance of the linear at low-dose
weeks just preceding his being awarded the Nobel Prize. modeling and risk assessment practices throughout the
Muller may have still believed that the linear dose– second half of the twentieth century to the present.
response model was the most appropriate. However, the
data of Caspari and Stern would not have supported a Acknowledgments Effort sponsored by the Air Force Office of
Scientific Research, Air Force Material Command, USAF, under
statement that there was ‘‘no escape from the conclusion grant number FA9550-07-1-0248. The US Government is authorized
that there is no threshold.’’ In fact, these data provided a to reproduce and distribute for governmental purposes notwith-
possible basis for such an escape. While Muller knew of standing any copyright notation thereon. The views and conclusions
the findings and their importance to the dose–response contained herein are those of the authors and should not be interpreted
as necessarily representing the official policies or endorsement, either
debate, the US government had yet to declassify the report expressed or implied, of the Air Force Office of Scientific Research or
by the time of the Nobel ceremony so he could not have the US Government.
explicitly cited it. However, given his unique insight into
the scientific foundations of threshold versus linearity Conflict of interest The author has no conflict of interest.
dose–response model debates and the importance to place
the matter on a strong scientific foundation, the most
intellectually honest position at the Nobel Prize Lecture
would have eliminated the ‘‘no escape’’ statement and References
emphasized the need for more research to determine the
nature of the dose–response in the low-dose zone. How- American Philosophical Society, Philadelphia (1946/1947a) Curt
ever, Muller chose not to do this, confidently concluding Stern Papers, Hermann J. Muller File, URL: [Link]
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One might suggest that after deeper reflection and toxicology: an old controversy revisited. Arch Toxicol
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