Abstract
Report 3 is devoted to the history, nature, and limitations of the epidemiological criteria for causality (“Hill’s criteria”). Based on material from the original publications of leading researchers of causality (A.B. Hill., M.W. Susser, K. Rothman, etc., 1950s–2019), from dozens of modern textbooks on epidemiology and carcinogenesis, from documents of international and internationally recognized organizations (UNSCEAR, BEIR, USEPA, IARC, etc.), as well as from many other sources, in part 2 of this report, Hill’s last four criteria are considered: biological plausibility, coherence with current facts and theoretical knowledge, experimental, and analogy. The theoretical and practical aspects for each criterion are presented: history of appearance, terminology, philosophical and epidemiological essence, applicability in various disciplines, and limitations. Factual examples are provided for each of the criteria, including data from radiation epidemiology and radiation medicine.
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Notes
For example, according to [44], for the drugs encainide and flecainide, after a mean follow-up period of ten months, 89 patients died: 59 from arrhythmias (43 with the drug vs. 16 with placebo; p = 4 × 10–4), 22 from non-arrhythmic cardiac causes (17 vs. 5; p = 0.01), and eight from noncardiac causes (3 vs. 5).
“A remedy which is known to work, though nobody knows why, is preferable to a remedy which has the support of theory without the confirmation of practice” [58].
“Many things which in theory ought to be highly effective turn out in practice to be completely useless” [58].
“It is not based on any theory of how the treatments might work” [59].
“The question to which we must always find an answer is not “should it work?” but “does it work?” (even if we do not know why)”[58].
The term “biologically implausible” can be found in the decision of the English public health authority of 1854, according to which evidence of cholera transmission through London water (researcher John Snow) is not supported by laboratory evidence [7]).
“Another factor is the widespread overemphasis on statistical approaches, with the concomitant tendency to neglect the fact that epidemiology is a biologic science concerned with disease in human beings” [60].
World Health Organization/International Program on Chemical Safety. Provides a formal framework for assessing data on pathways of causal key events leading to adverse health outcomes [78].
For example, in the manual by M. Szklo and F.J. Nieto from 2019 (fourth edition [65]), the “Coherence,” “Specificity,” and “Analogy” criteria are removed from the list of criteria for causality. It is stated that “We, like other authors (L. Gordis from 2014 [67], K.J. Rothman and S. Greenland from 2005 [50]), believe that these three guidelines are useless for the following reasons: “Coherence” is difficult to distinguish from “Biological Plausibility…”.
“Coherence is an ultimate and yet not a necessary criterion for causality” [67].
“Coherence is comforting; incoherence by itself is often not destructive of a hypothesis but emphasizes gaps in scientific understanding” [86].
“All scientific work is incomplete—whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action that it appears to demand at a given time” [1].
This conclusion should not be taken too seriously, it is kind of sophism. First, we do not have data on the dynamics of chrono-changes for all world cohorts of workers in the nuclear industry (an example is given for workers in England, however, for all [117]). Second, absolute (not relative) risks are more important, which, compared with previous decades, obviously decreased along with the background values for the general population. Third, as the period of employment lengthens, the “healthy worker effect” becomes smaller [117]. However, for the media and even ordinary scientific consciousness, this paradox may seem socially significant.
Rem—roentgen equivalent man; 1 rem = 0.01 Sv [121].
“Although experimental tests can be much stronger than other tests, they are not as decisive as often thought, because of difficulties in interpretation” [122]. Anyone who has received experimental work for review will agree with this. Sometimes it is the interpretation of the authors that is the basis (sometimes incorrect and subjective) of the conclusions, and the essence of the methodology (by the meaning of the objective) is not always deepened.
“This simple fact is especially important to epidemiologists, who often face the criticism that proof is impossible in epidemiology, with the implication that it is possible in other scientific disciplines. Such criticism may stem from a view that experiments are the definitive source of scientific knowledge. Such a view is mistaken on at least two counts. First, the nonexperimental nature of a science does not preclude impressive scientific discoveries; the myriad examples include plate tectonics, the evolution of species, planets orbiting other stars, and the effects of cigarette smoking on human health. Even when they are possible, experiments (including randomized trials) do not provide anything approaching proof, and in fact may be controversial, contradictory, or irreproducible” [50].
“Some experimental scientists hold that epidemiologic relations are only suggestive, and believe that detailed laboratory study of mechanisms within single individuals can reveal cause–effect relations with certainty. This view overlooks the fact that all relations are suggestive in exactly the manner discussed by Hume: even the most careful and detailed mechanistic dissection of individual events cannot provide more than associations, albeit at a finer level. Laboratory studies often involve a degree of observer control that cannot be approached in epidemiology; it is only this control, not the level of observation, that can strengthen the inferences from laboratory studies. Furthermore, such control is no guarantee against error. All of the fruits of scientific work, in epidemiology or other disciplines, are at best only tentative formulations of a description of nature, even when the work itself is carried out without mistakes” [50].
Above, it was pointed out to the broad, literal citation of this Hill’s “credo” in foreign publications. A Google search for the exact combination of words gives about 1.65 million sources for the quote; the statement is considered, among other things, within the framework of the “precautionary principle.”
With regard to Hill’s “Experiment” criterion, [51] states “To different observers, experimental evidence can refer to clinical trials, to laboratory experiments with rodents or other nonhuman organisms, or to both.”
“It is not clear what Hill meant by experimental evidence. It might have referred to evidence from laboratory experiments on animals, or to evidence from human experiments [122].
For example, in the early 1980s, the non-steroidal anti-inflammatory drug benoxaprofen was developed for the treatment of arthritis/musculoskeletal pain [135, 145] (under the commercial names Opren in Europe and Oraflex in the United States [135]). A large-scale RCT in a population aged 18–65 demonstrated its efficacy, and the drug began to be promoted through aggressive marketing in the United Kingdom and the United States. However, thousands of elderly patients experienced severe side effects, and many deaths from hepatorenal insufficiency were registered [135, 145] (according to a parliamentary report, 77 deaths in the United Kingdom alone [146]).
The history of the development of the RCT can be found on the website of the thematic “James Lind Library” (Edinburgh).
“In epidemiology, scientific investigations often proceed inductively” [166].
“Inductive methods constitute the substance of standard epidemiological texts such as Rothman’s, Kahn’s, Miettinen’s, etc.” [167].
“Certainly epidemiologists are in the habit of generating hypotheses by induction from the arrays of descriptive data and existing knowledge with which their studies are bound to begin” [168].
“My reply is that epidemiological inferences are but a part of a wider (inductive) epidemiological process” [169].
“Often experimental epidemiology is simply equated with randomized controlled trials” [47].
“...the book will be addressing issues relating to observational epidemiology—not experimental epidemiology.” “Almost all studies conducted by field epidemiologists are observational studies, in which the epidemiologists document rather than determine exposures” [179]. This means “natural,” semi-experiments.
“Although some researchers consider clinical trials that employ experimental interventions part of epidemiology, this is not the common view” [175].
“Elevate “vaguely formulated expectations” into theory, rename the inductive reasoning process “reproduction,” and the transformation is accomplished” [187].
“Adequate human data are the most relevant for assessing risks to humans. When sufficient human data are available to describe the exposure–response relationship for an adverse outcome(s) that is judged to be the most sensitive effect(s), reference values should be based on human data” [193].
“Human data form the most direct evidence for an association between health effects and exposure to chemicals” [194].
“Human data are required for conclusions that there is a causal relationship between an exposure and an outcome in humans. Experimental animal data are commonly and appropriately used in establishing regulatory exposure limits and are useful in addressing biological plausibility and mechanism questions, but are not by themselves sufficient to establish causation in a lawsuit. In vitro data may be helpful in exploring mechanisms of toxicity but are not by themselves evidence of causation” [133].
“Experimental evidence in humans would indeed constitute proof of causation…” [54].
“A number of learned and progressive jurists have recognized that, in the presence of meaningful epidemiologic studies, the contrived exposure situations of animals in laboratories produce information of relatively little value” [195].
“…human data are the most valid metric to determine human causality” [196].
Even earlier, at the beginning of the 19th century, F. Magendie (1783–1855; France) developed an approach in the field of pharmacology and therapy based on animal tests [57].
In 1938, a venereologist from Birmingham published in a provincial journal a comparative study of three drugs for the treatment of syphilis: the English “Novostab,” the American “Mapharside,” and the German “Neosalvarsan.” The German drug proved to be the most effective in the ability to clear syphilitic ulcers from spirochetes in patients. The UK MRC’s approach, however, was to compare the new arsenic compounds with the standard formulations of salvarsan and neosalvarsan using a trypanosomal test in mice (the so-called “experimental epidemiology”). The possibility of a contradiction between the standard MRC approach and direct human data obtained by E.W. Assinder (together with the “unpatriotic” nature of his conclusion) then alerted not only the indicated organization but also the Department of Health Care of the United Kingdom [180].
For example, in 2006, a phase I study of CD28TGN1412, a monoclonal antibody against the CD28 T-lymphocyte receptor [204–207], developed by the German company TeGenero, was conducted in the United Kingdom in eight volunteers [206]. The drug was supposed to be used in autoimmune diseases and leukemias [204, 206, 207]. Preclinical trials in primates and rabbits showed no side effects [207]. Two volunteers received a placebo [206], and six received only 1/500 of the dose estimated in primates [204]. In all six volunteers, the drug elicited a severe “cytokine storm” response [204–206], leading to multiple organ failure and other severe effects [205–207]. The swelling was so great that the trial was named “The Elephant Man Clinical Trial” [206]. One participant developed dry gangrene followed by amputation of part of the foot and toes (Raynaud’s phenomenon). Cognitive and many other serious impairments were observed years after the experiment, although all subjects survived [205].
“Once again looking at the obverse of the coin, there will be occasions when repetition is absent or impossible and yet we should not hesitate to draw conclusions” [1].
“Because the only ethical experiments concerning causality in humans are experiments in prevention” (Doll, R., 1978) [107].
“Ethically, the individual involved must have the potential to benefit and yet there must be uncertainty on the question posed. For risk factors, as opposed to protective factors, there may be no such benefit” [20].
“There must be the expectation that in the population under study the radiation will lead to an improvement in health status relative to any alternative treatment” [30].
A 2018 Japanese article [212] reports the following unpublished RCT data for a “hormesis study.” N. Shimizu from Osaka University analyzed the performance of volunteers who slept daily on special radioactive mats containing 228Ac and 77Br with a background radiation of 5 µGy/h. The same mats, but without radioactivity, served as controls. Healthy volunteers (30 males and 30 females, 22–48 years old, mean age 32 years) were randomly divided in half into a “hormesis” group and a placebo group. After three months (cumulative dose obtained over 3 mGy), the reactive oxygen species levels were, on average, 3.1 and 9.4% lower than the baseline for the placebo and hormesis groups, respectively, in men, and 3.1 and 8.5% lower in women (in both groups, p < 0.05). “Sleep delay, as well as physical, psychological, and neurosensory status improved in the hormesis group compared with the placebo group” [212]. The data were presented at the Japanese Society for Radiation Oncology Symposium (Symposium for Cancer Control) in Nagoya in 2017. In another similar RCT performed by N. Shimizu on 40 men, an increase in the IgA level in saliva and a lengthening of the period of non-REM sleep were observed in the experimental group [212]. It is hardly possible to draw serious conclusions from this study, but the very fact of a real RCT with irradiation of healthy people is still unique.
“Clinical observations can be made (and to be of any use, they must be made) just as accurately as laboratory observations; but in the human subject, observations cannot be as readily controlled, the conditions cannot be so easily kept uniform or varied; in one word, the problems cannot be analyzed as they can be in the animal” [222].
The threshold for the most radiosensitive deterministic effect known to all radiobiologists—temporary suppression of spermatogenesis—in most sources, including Russian manuals, corresponds to 0.15 Gy (no references are given). In other, also significant publications, 0.1 Gy is reported (for example, [226, 227]). Few references are made to the two original studies [228, 229] (and the summarizing review [230]), and the fact that these data, which are still reference data, were obtained in two clinical trials (1963–1973) on “volunteers” (22–52 years) in prisons of the United States (Washington and Oregon) is mentioned almost nowhere. The testes of the participants laying on a special bed were locally repeatedly irradiated with X-rays, up to accumulated doses of 75 mGy–6 Gy. In these experiments, the threshold of temporary suppression of spermatogenesis in humans was revealed (punctures for biopsy were taken periodically), which constituted approximately 0.08–0.1 Gy [228–230]. The prerequisites for the experiment were the need to protect the “family jewels” (as an American Air Force colonel put it) in pilots of nuclear-powered aircraft constructed in the 1950s and in astronauts in the 1960s. In 1963, at a conference in Colorado, the leading US endocrinologist C.G. Heller said: “If everyone is interested in what happens with a person when the testes are irradiated, then why should we fuss with mice, beagle dogs, canaries, etc.? If you need to know about the human situation, why not experiment on humans?” [231]. In the early 1970s, these experiments were stopped for ethical reasons, and in 1994 a commission created by B. Clinton investigated all circumstances, including the health and subsequent life costs of many “volunteers” [231]. These experiments cannot be called RCT with radiation, they are just CTs on healthy volunteers.
“...it would be unethical to deliberately expose healthy human volunteers to a lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substance…” [215].
“Approval under the Animal Rule can be pursued only if human efficacy studies cannot be conducted because the conduct of such trials is unethical and field trials after an accidental or deliberate exposure are not feasible” [215]. “Furthermore, field trials to study a product’s effectiveness after an accidental or intentional exposure are not feasible” [232].
“In the absence of adequate data on humans, it is biologically plausible and prudent to regard agents for which there is sufficient evidence of carcinogenicity in experimental animals as if they presented a carcinogenic risk to humans” [127].
“Although this association cannot establish that all agents that cause cancer in experimental animals also cause cancer in humans, it is biologically plausible that agents for which there is sufficient evidence of carcinogenicity in experimental animals also present a carcinogenic hazard to humans” [214].
“This guidance provides information and recommendations on drug and biological product development when human efficacy studies are not ethical or feasible” [215].
“The Animal Rule states that for drugs developed to ameliorate or prevent serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic substances, when human efficacy studies are not ethical and field trials are not feasible, the FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is reasonably likely to produce clinical benefit in humans” [215].
“Marketing approval for new radiation countermeasures for which human efficacy studies are not feasible or ethical would be based on animal efficacy studies and phase I safety data in healthy volunteers. Under this animal rule, human efficacy trials of radiation countermeasures could be bypassed through a shortened but stringent FDA approval pathway that demonstrates drug efficacy in two animal species predictive of human responsiveness, a sound understanding of the mechanisms of action, and safety in humans” [232].
“The mode of action is the way that the mechanism ultimately affects the entity.” An example from aquatic ecology is given: the binding of copper ions in the gills disrupts ion regulation, leading to a decrease in the concentration of sodium and chloride in the blood, which affects its viscosity (mechanism), and this, in turn, causes a stop (arrest) of the fish heart (mode of action) [239].
We plan to consider the omnipresence of Hill’s causality criteria for evidence both in biomedical disciplines and in a wide variety of epidemiology (classical, field, molecular, judicial, behavioral, psychiatric, social, etc.; all such disciplines exist), in teratology, neuropsychiatry, jurisprudence, economics, etc., in Review 4. Here we see that Hill’s criteria in the fields of ecology and toxicology even reached animal studies. So to speak, they are “universal values.” This, as already noted in Part 1 of this report [9], is due to the fact that the inductive–deductive rules for establishing causal dependences are the same for the human mind and are a consequence of the laws of logic, being rooted in the constructions of philosophers of past centuries, mainly D. Hume and J. Mill [2, 3].
Apparently, the most striking example of how the absence of animal testing ends up after the introduction of a drug into practice was the mass poisoning with diethylene glycol in 1937 in the United States [192, 242–244]. This was the first reported case of human toxicity of this compound [242]. Children and adults were poisoned not because they “drank antifreeze” (which includes this compound), but because they took a sulfanilamide syrup “with raspberry flavor” [243], called “Elixir Sulfanilamide,” in which the solvent was 72% diethylene glycol (sulfonamides are insoluble in water, and the company wanted to make a syrup) [192, 242–244]. At that time, there was no law in the United States prohibiting the marketing of untested drugs [244], so the “elixir” passed only organoleptic testing [192], without animal testing, and was put on sale [192, 242–244]. The drug was received by 353 patients, 105 of which (34 children and 71 adults) died of renal failure [242]. The chemist from the company who thought of using 72% (!) diethylene glycol as a solvent committed suicide [244]. As a result, the FDA passed a law in 1938 on mandatory testing of drugs on animals [242, 243]. Note that, unlike thalidomide of the 1950s discussed above, for which animal experiments did not show teratogenicity, for Elixir Sulfanilamide such experiments were not performed at all, despite the fact that, as was stated, as early as at the beginning of the 19th century F. Magendie started using animal testing of drugs [57].
“Resorting to animal experimentation can reduce some of these problems but introduces new ones, because an inference from results in animals to effects in humans is far from trivial” [249].
“Courts are recognizing that the effort to apply laboratory animal findings to man is not an extrapolation-even though it is commonly referred to as such. Rather it is a generalization, primarily a subjective process, in which a number of undefended assumptions are implicitly invoked” [195].
However, this analytical review [250] of 121 animal-to-human extrapolation studies of the effects of medicines, interventions, and just “events” actually gives a different picture, despite vague conclusions. Our digitization (GetData Graph Digitizer, ver. 2.26.0.20) and data calculations from diagrams and box-plots from [250] (Figs. 2, 4, 7) showed the following. Successful extrapolation (by 50–100%) corresponds to 67% of the sample (75–100%–27%); by the median data, the intervention studies and trials were extrapolatively adequate for 64 and 79%, respectively. Finally, for certain species, the median extrapolation success rates were 82% for mice, 73% for rabbits, 67% for rats, 64% for primates, 54% for dogs, and 33% for guinea pigs. For the pig, there was only one study in [250], and extrapolation success was 100%.
M.W. Susser in 1986 [18] provides an example of the artificiality of the design of animal experiments, which may not be replicable in human observational studies. In 1966, it was found that, in rats, acute protein deficiency in the early stages of development leads to depletion of brain cells. This fact has led to many epidemiological studies of children to test the impact of early malnutrition on mental development. But such works could not and did not test the effects of acute nutritional deficiency; instead, they assessed the effects of permanent and chronic malnutrition. Thus, until the developmental effects of acute prenatal fasting during fasting were studied, adequate evidence for experiments on rats could not be obtained.
“Replacing a test on a living organism with a cellular, chemicoanalytical, or computational approach obviously is reductionistic” [255].
“In vitro studies that test mechanistic pathways and demonstrate the biological role of an agent in disease progression may result in knowledge that can be used to predict potential human health outcomes in a much more time-efficient manner than human studies, particularly for adverse outcomes with a long latency period” [113].
“Risk assessments would eventually be conducted using mathematical models of toxicity pathways (TP models) to estimate exposures that will not cause biologically significant perturbations in these pathways” [258].)
“Toxicity pathways models are unlikely to contribute quantitatively to risk assessments for several reasons, including that the statistical variability inherent in such complex models severely limits their usefulness in estimating small changes in the response and that such models will likely continue to involve empirical modeling of dose responses” [258].
“Analogy: in some circumstances, it would be fair to judge by analogy. With the effects of thalidomide and rubella before us, we would surely be ready to accept slighter but similar evidence with another drug or another viral disease in pregnancy” [1].
Later, it turned out that W.G. McBride had falsified animal experiments with a new anti-nausea drug [263]. In our opinion, he could also have been guided by good intentions here, being frightened by thalidomide, although, of course, such methods are inexcusable even within the framework of the “precautionary principle.”
“...when one of a class of causal agents is known to have produced an effect, the standards for evidence that another agent of that class produces a similar effect can be reduced” [64].
“Analogy can be helpful, although the help seems limited since anybody with a little creativity can probably dream up an analogy!” [130].
“Analogy, then, becomes one way to invent a hypothesis, although it is a bit unimaginative. A Popperian alternative to analogy would be creative inventiveness” [272].
Howard Frumkin is Professor Emeritus of Environmental and Occupational Health Sciences at the University of Washington School of Public Health; Professor and Chair of Environmental and Occupational Health at Emory University’s Rollins School of Public Health, and Professor of Medicine at Emory Medical School from 1990–2005. https://deohs.washington.edu/faculty/howard-frumkin. Accessed November 11, 2020.
“Whatever insight might be derived from analogy is handicapped by the inventive imagination of scientists who can find analogies everywhere. At best, analogy provides a source of more elaborate hypotheses about the associations under study; the absence of such analogies only reflects a lack of imagination or experience, not falsity of the hypothesis” [50].
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This study, which was carried out within the framework of the broader budgetary theme of the R&D of the Federal Medical-Biological Agency of Russia, was not supported by any other sources of funding.
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Koterov, A.N. Causal Criteria in Medical and Biological Disciplines: History, Essence, and Radiation Aspect. Report 3, Part 2: Hill’s Last Four Criteria: Use and Limitations. Biol Bull Russ Acad Sci 49, 2184–2222 (2022). https://doi.org/10.1134/S1062359022110115
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DOI: https://doi.org/10.1134/S1062359022110115