Correspondence
THE EPISTEMOLOGICAL LIMITS OF
EPIDEMIOLOGY FOR INFERRING RISKS
AT LOW DOSES
Dear Editors:
MANY COLLEAGUES in our community have read the very in-
teresting and sophisticated analysis of Kocher et al. on the
dose and dose-rate efficiency factor (DDREF) (Kocher et al.
2018), Wakeford’s letter about it (Wakeford et al. 2019),
and Kocher’s response (Kocher et al. 2019) to Wakeford’s
letter. These interactions confirm the erudite mathematical
treatment, sometimes of data and sometimes of inferences,
reached by radioepidemiology. Notwithstanding the depth
of these scholarly exchanges, they do not resolve a simple
but fundamental conundrum: the epistemological limits of
epidemiology for inferring risks at low doses and, in partic-
ular, for the notion of DDREF.
The science of epidemiology is expected to deal with
epidemics (from Greek ἐpί “upon” and dh~ moς “people”)
of disease; namely, with the widespread occurrence of an
ailment upon people. Its role is to study and assess scientifi-
cally and objectively the main parameters defining an epi-
demic, such as the incidence of the relevant disease.
Radioepidemiology is the branch of epidemiology assessing
epidemics of health effects associated with radiation exposure.
Thus, following the epidemic of leukemia and solid cancers in
the aftermath of the nuclear bombing of Hiroshima and
Nagasaki, it was expected and proper that radioepidemiology
tried to understand and quantify scientifically the parameters
of that epidemic—which it did. Similarly, there was an epi-
demic of pediatric thyroid cancers in the aftermath of Cherno-
byl, which was also properly assessed by radioepidemiology.
But it seems that there is not a manifest epidemic attrib-
utable to low-dose exposure situations.1 Circumstances
where people incur doses comparable to typical background
doses do not appear to be causing any widespread occur-
rence of any disease. Therefore, it is reasonable to ask what
the role of radioepidemiology is in these situations. Is it to
predict a potentially occult epidemic, however untestable
these predictions might be? The proper answer to this ques-
tion is at the root of the DDREF issue addressed in the
Kocher/Wakeford exchange.
0017-9078/19/0
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DOI: 10.1097/HP.0000000000001085
828
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Since radiation health effects among the Hiroshima
and Nagasaki survivors developed, it has become appealing
to use the parameters derived from that epidemic for deriv-
ing subjective inferences of health effects for low-dose ex-
posure situations—in spite of the fact that at such low
doses, neither was an epidemic identified nor did factual
and reliable objective data of health effects exist. This deri-
vation, however, falls outside the epistemological limits of
epidemiology. Epistemology studies the theory of knowl-
edge, especially with regard to its methods, validity, and
scope, and attributing effects at dose levels that are outside
the reach of epidemiology is epistemologically question-
able. Radioepidemiology can provide vast knowledge on ra-
diation effects, based on those distinct situations where
there was an epidemic, but the extrapolation of such knowl-
edge to situations for which knowledge is an untestable con-
jecture is an epistemological error.
In such low-dose regions, radiobiology (i.e., the science
that studies the effects of radiation on biological systems) can
be helpful in providing fundamental knowledge on the mech-
anisms of radiation-induced health effects. These mecha-
nisms are extremely complex and have been reported by
the United Nations Scientific Committee on the Effects of
Atomic Radiation (UNSCEAR).2 Analyses of biological
mechanisms at various radiation doses have been recorded
in myriads of scientific papers. Reporting at various dose
rates is least abundant, and information on the effects of
dose-rate changes is limited (e.g., Brehwens et al. 2010).
UNSCEAR (2012) concluded that while mechanistic under-
standing of effects is improving, many studies remain primar-
ily observational, their reporting is mixed in outcome, and
1
Most recently, radioepidemiology has been dealing with suspected
radiation epidemics in, inter alia, occupationally exposed workers, popula-
tions subjected to malpractice involving radioactive residues, patients ex-
posed during radiodiagnosis and radiotherapy, and people exposed to
radon gas. Inhalation of radon and its decay products has been recognized
as carcinogenic, and there is a long story of epidemics of lung cancers at-
tributable to radon (mainly in cohorts of miners), which also show a large
synergetic effect from smoking. For residential radon the issue is still un-
der debate; an epidemic among residents is not apparent, and depending
on the data which are analyzed, attributable detrimental effects, no effect,
and even hormetic effects have been reported by various epidemiological
studies. UNSCEAR is studying this issue thoroughly, and its estimates
are expected soon.
2
Besides direct and indirect radiation interactions with cells leading
to carcinogenic effects, the mechanisms include genomic instability, by-
stander effects, abscopal effects, adaptive responses, clastogenic plasma
factors, reactive oxygen metabolism and mitochondrial dysfunction,
and the impact of genetic polymorphisms and gene and protein expres-
sion. Tissue-level phenomena and systems biology approaches have
also been investigated, as well as radiation-induced perturbation of im-
mune function or induction of inflammatory reactions.
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 Correspondence
there is little of the coherence required of robust data that can
be used confidently. Moreover, there is as yet no unambigu-
ous indication of a causal association of these mechanistic
phenomena with radiation-related disease; indeed, some ap-
pear in vitro but may not operate at low doses in vivo.3
In sum, an old UNSCEAR dictum remains valid, namely:
(1) in spite of the large body of new radiobiological informa-
tion available, considerable disagreement remains concerning
any definitive relationship between the biological mecha-
nisms studied and the observed health effects attributable
to radiation; and (2) only direct epidemiological observa-
tions, which incorporate all biological elements, could in-
form on the attributability of health effects to low-dose
exposure situations (UNSCEAR 2008b).
Therefore, the onus for addressing scientifically the
low-dose problem remains mainly on radioepidemiology
rather than radiobiology. However, as described before,
radioepidemiology also has epistemological constraints,
and the attribution of health effects to low-dose radiation ex-
posure situations seems to fall outside those limits. These
constraints include epistemic4 and statistical power limita-
tions, which have been summarized by UNSCEAR
(2008a). Under current biological assumptions, the size of
the cohort required to detect a radiation effect with adequate
statistical power will be approximately proportional to the
inverse of the dose squared, and for low doses, such cohort
sizes become so large that a meaningful epidemiological
study becomes unfeasible.
Therefore, the difficult decisions of whether and how
to protect people against radiation exposure, in situations for
which there is no evidence of health effects, fall outside the
epistemological limits of radiobiology and radioepidemiology.
The knowledge derived from these sciences can serve as a rel-
evant input, but such decisions are the remit of another kin dis-
cipline: radiation protection. The International Commission on
Radiation Protection (ICRP) assembles senior experts who are
expected to provide relevant advice on radiation protection of
people incurring those dose levels for which health effects are
not attributable to the exposure, although potential risks might
be inferred (the distinction between the attribution of health ef-
fects and the inference of risk was established by UNSCEAR
[2015] and is further discussed elsewhere [González 2014]).
3
Radiobiology has also searched for biological indicators of radia-
tion exposure in specialized bioassay specimens (hematological and cyto-
genetic samples). However, it is recognized that the presence of such
biological indicators does not necessarily mean that health effects will be
experienced. A reliable biological indicator that could unequivocally attri-
bute health effects to low-dose radiation exposure has not yet been discov-
ered; moreover, should such a bioassay be found, it may not resolve the
issue of attributability of effects to low doses due to the pervasive presence
of background radiation—it will be hard to find an indicator able to distin-
guish 4between low doses from a source and low doses from background!
Epistemic limitations include transfers between populations, inter-
actions of carcinogens, genetic susceptibility, dose protraction or fraction-
ation, dose response, effect of age at exposure, latency, and time since
exposure.
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829
It is to be noted that many radioepidemiologists and ra-
diobiologists, such as those mentioned in Richard Wakeford’s
letter, also bear radiation protection responsibilities; however,
they are providing recommendations under a different “hat”:
rather than radiobiologists or radioepidemiologists, they ad-
vise as radioprotectionists. In any case, as discussed in a recent
paper (Wieland and González 2018), the ultimate decisions on
protection against low-dose radiation exposure are made nei-
ther by radioepidemiologists nor radiobiologists, nor even by
radioprotectionists; it rather is legislators and regulators who
are the ultimate decision makers. They ought to convert the
available scientific evidence into commensurate legislation
and regulations using common sense rather than biological
and epidemiological conjectures.
Coming back to the contributions of Kocher, Wakeford,
and colleagues, the above described confusion on the role
and limitations of radiobiology and radioepidemiology is at
the root of the serious and puzzling epistemological error
of creating and developing the concept termed DDREF (an
issue discussed by González [2017]). The use of the DDREF
concept for radiation risk estimates at low doses is arguable,
clearly controversial, and epistemologically questionable; its
use has turned out to be unneeded, and it can therefore be
abandoned. For a radiation exposure situation for which there
has been an epidemic, and therefore for which there is avail-
able epidemiological information that can be scientifically
tested (namely, is confirmable and verifiable and therefore
falsifiable), radiation risks can continue to be attributed in
terms of frequentist probabilities, i.e., as limits of the relative
frequency of the effects occurring on the basis of the measur-
able incidence of disease. Conversely, for a radiation expo-
sure situation where there is not an epidemic (i.e., for
which direct scientific evidence of effects is unavailable or
unfeasible to obtain), notional radiation risks might need to
be inferred on the basis of indirect evidence, scientific rea-
soning, and professional judgment, which should be aimed
at estimating their plausibility in terms of subjective
probabilities or degrees of belief among experts, such
as those on ICRP Committee 1. For this subjective judg-
ment, radioepidemiological input with objective data from
epidemic situations plus robust radiobiological information
should be welcomed, but an artificial and epistemological
controversial DDREF is not needed.
The author declares no conflicts of interest.
ABEL JULIO GONZÁLEZ
Autoridad Regulatoria Nuclear
Buenos Aires, Argentina
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