Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=bher20 Human and Ecological Risk Assessment: An International Journal ISSN: 1080-7039 (Print) 1549-7860 (Online) Journal homepage: http://www.tandfonline.com/loi/bher20 A quantitative risk assessment for chronic traumatic encephalopathy (CTE) in football: How public health science evaluates evidence Adam M. Finkel & Kevin F. Bieniek To cite this article: Adam M. Finkel & Kevin F. Bieniek (2018): A quantitative risk assessment for chronic traumatic encephalopathy (CTE) in football: How public health science evaluates evidence, Human and Ecological Risk Assessment: An International Journal To link to this article: https://doi.org/10.1080/10807039.2018.1456899 Published online: 25 Apr 2018. Submit your article to this journal View related articles View Crossmark data A quantitative risk assessment for chronic traumatic encephalopathy (CTE) in football: How public health science evaluates evidence Adam M. Finkel a and Kevin F. Bieniek b a Environmental Health Sciences, University of Michigan School of Public Health Ann Arbor, Michigan, USA and Wharton Risk Management and Decision Processes Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA; b Neuroscience, Mayo Clinic College of Medicine and Science, Jacksonville, Florida, USA ARTICLE HISTORY Received 5 February 2018 Revised manuscript accepted 21 March 2018 ABSTRACT How should science and policy interpret the recent fi nding that 110 of 111 former National Football League (NFL) players had brain pathology known as chronic traumatic encephalopathy (CTE) at autopsy? Some physicians view this (and related epidemiologic and mechanistic evidence) skeptically, emphasizing that the association between repeated head trauma (RHT) and CTE may be artifactual, that this “ incidence ” is biased by self-selection of players with cognitive or emotional symptoms, and that even if RHT causes CTE, the lesions themselves may be inconsequential. Public health scientists look at this emerging evidence quite differently; in particular, they tend not to fall prey to certain illogical arguments justifying inaction. We present a quantitative risk assessment showing that even accounting for the non- representativeness of the 110 cases, the risk of CTE in the NFL workforce amply meets both parts of the test for “ a signi fi cant risk of material impairment of health ” that would permit the U.S. Occupational Safety and Health Administration to intervene to reduce RHT exposure. We further conclude that according to available evidence, CTE is a public health problem, and that lawyers and physicians need to understand that this conclusion is based on standards of evidence at least as long- standing and robust as their own. KEYWORDS epidemiology; OSHA; quantitative risk assessment; head trauma; science-policy; chronic traumatic encephalopathy (CTE) Introduction Scienti fi c consensus about the nature and magnitude of environmental and occupational health risks is often elusive, but accruing evidence generally helps experts converge if not agree. This is not so in the case of chronic traumatic encephalopathy (CTE) as a possible grave health risk of occupations and avocations that involve repeated head trauma (RHT) – occupations that include professional contact sports (notably American football) and jobs in the logging, commercial driving, fi re fi ghting, and military sectors (Tiesman et al. 2011). In recent years, as several case series of former National Football League (NFL) players with CONTACT Adam M. Finkel a fi nkel@upenn.edu Clinical Professor of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA and Senior Fellow, Wharton Risk Management and Decision Processes Center, University of Pennsylvania, Philadelphia, PA, USA. © 2018 Taylor & Francis Group, LLC HUMAN AND ECOLOGICAL RISK ASSESSMENT https://doi.org/10.1080/10807039.2018.1456899 CTE, epidemiologic studies of CTE incidence in persons with and without history of RHT, and mechanistic studies relating RHT and CTE have appeared in the literature, scientists, clinicians, and advocates have been expressing increasingly polar and irreconcilable posi- tions with respect to the three most basic risk-related questions: (1) is CTE causally related to RHT, or are the two related by non-causal association or by mere coincidence?; (2) if RHT contributes to CTE, how likely is a given amount of exposure to RHT to cause such harm? (and more speci fi cally, what is the average CTE risk among NFL players given their exposures, and hence what is the expected number of CTE cases in this cohort?); and (3) how severe are the neurological and other consequences of CTE to those af fl icted with these lesions? 1 The authors – one a pioneer in methods of quantitative risk assessment (QRA) and cost – bene fi t analysis (and a former chief regulatory of fi cial at the U.S. Occupational Safety and Health Administration (OSHA)) and the other a neuroscientist with a special focus on CTE – observe that there is a large and growing disconnect between experts who believe that the evidence is ample to justify individual caution and possible regulatory action or “ nudges ” (Sunstein and Thaler 2008) to limit RHT, versus those who believe the “ science remains in its infancy ” (Carey 2016) and that no such conclusions can be drawn. Outside the peer- reviewed literature, diametrically clashing opinions on these questions are on prominent dis- play, and feature poignant stories by next-of-kin (Carpenter 2017) and by recently retired players dealing with what they consider to be early symptoms of disease (Utecht and Tabb 2017; Kelly 2018), contrasting with indirect denials from the League pointing out to a group of reporters, for example, that “ the average NFL player lives fi ve years longer than you ” (Gantt 2017) 2 . This article focuses on the nearly-as-wide spread of opinion within the pub- lished literature. With respect to the fi rst of the three basic questions above, current conclusions about the relationship between RHT and CTE run the wide gamut from “ [repeated head trauma], with or without symptomatic concussions, can alter the structure and function of the brain to potentially underpin cognitive, behavior and mood de fi cits observed in some former ama- teur and professional football players ” (Alosco et al. 2017) to “ Beyond identifying the exis- tence of abnormal tau protein in a person ’ s brain, researchers know very little about CTE ” (In re Nat ’ l Football League Players Concussion Litigation 2015). With respect to the second question, assertions about the eventual excess incidence of CTE among retired NFL players range from the prediction that “ a shockingly high percentage ” of NFL players will develop CTE (Fainaru-Wada and Fainaru 2013) to “ the reporting of CTE in former professional American football players has led to widespread speculation far beyond the conclusions that can be drawn ... ; there is no credible data with which to establish the incidence or prevalence of CTE ” in the NFL cohort (Maroon et al. 2015). And with respect to the clinical severity of CTE lesions to the individual affected, conclusions range from “ The clinical features [of 1 Note that we array these questions according to the time-honored paradigm fi rst codi fi ed in the early 1980s (National Research Council 1983), in which quantitative risk assessment begins with the “ hazard identi fi cation ” stage (what health effect(s) can the substance or agent induce?), proceeds in parallel through exposure assessment (how much exposure to the hazard do humans undergo?) and dose – response assessment (what is the function relating exposure to probability-of- harm?), and concludes with the “ risk characterization ” stage (how large and how severe are the consequences of the popula- tion ’ s exposures?). 2 As a reviewer pointed out, this observation is both unremarkable (NFL players surely bene fi t from the “ healthy worker effect ” and are expected to live longer than average merely because they were once fi t enough to make an NFL team) and incom- plete (it says nothing about any quality-of-life differences between NFL players and the general population). 2 A. M. FINKEL AND K. F. BIENIEK CTE] include impairments in mood (for example, depression and hopelessness), behavior (for example, explosivity and violence), cognition (for example, impaired memory, executive functioning, attention, and dementia), and, less commonly, motor functioning (for example, parkinsonism, ataxia, and dysarthria) ” (Montenigro et al. 2014), to the diametrically opposite conclusion that CTE lesions are “ tiny abnormalities [that] might not have any speci fi c clini- cal signi fi cance ” (Noy et al. 2016) or that they are “ merely an immuno-histochemical curios- ity ” (Schnabel 2016). 3 Some of these chasms are doubtlessly widened by con fi rmation bias – the selective or preferential marshaling of evidence to bolster preconceptions (Kahan 2013) – and of course it is possible that fi nancial considerations, tribal loyalties, or personal agendas can have a profound in fl uence on those preconceptions (Haidt 2012). It is also possible that we are exaggerating the size and characteristics of the cadre of CTE skeptics – that for this particu- lar disease and possible cause, only a small subgroup of the physician/legal observers see things very differently from the public health orientation. 4 Nevertheless, we believe that much of this and other controversies stems from a fundamental disconnect between how most public health scientists, as opposed to some clinicians or tort lawyers, amass and interpret evidence of association, of risk, and of harm. In particular, the type and quality of evidence sought and deemed useful to avoid errors of one type only (false positives, or Type 1 errors) in clinical diagnosis and legal compensation for speci fi c causation may be misleading and counterproductive in public health evaluation. This article therefore uses the disparate interpretations about CTE as a real-time, evolving example of the need for better communication across the range of scienti fi c and other special- ties. We suggest that some clinicians and lawyers need a much better understanding of how public health professionals look at evidence of causality, probability, and severity, not because the public health burdens of proof are “ lower, ” but because they are fi t for different purposes. Most generally, the science can indeed “ be in its infancy ” for the purpose of estab- lishing speci fi c causation at the individual level, but at the very same time it can be more than ample to establish a public health concern and a worthy target of regulatory attention. 5 And speci fi cally in the case of CTE, as we will show, a large case series (despite being derived from a likely nonrepresentative convenience sample) can give a skewed picture of the pre- vailing risk of a disease, but at the same time it can be more than ample to establish a public health concern and a risk whose central estimate is clearly “ signi fi cant. ” On the other hand, we also urge public health professionals to consider more seriously what their orientation cannot offer society in terms of our understanding of speci fi c causa- tion, mechanisms of action, and perhaps even the ability of public health interventions to 3 For a recent review article discussing the evidence linking RHT to CTE as well as some of the possible weaknesses in the cur- rent knowledge base, see Asken et al. (2017). 4 In this case, it may be that the most parsimonious division lies between physicians whose specialty is not neuropathology (e.g., concussion specialists, psychiatrists, orthopedists) and those who specialize in neuropathology and whose approach to evaluating evidence may tend to be similar to the public health orientation. 5 For a prominent example of this, consider the case of smoking and lung cancer: 54 years after the landmark Surgeon Gener- al ’ s Report (US Dept of HEW 1964), we still do not know with certainty which constituent(s) of tobacco smoke cause lung cancer, which target(s) in the genome are affected, the molecular mechanism by which any constituent exerts its toxic effect, whether genetic correlates place speci fi c individuals at much higher or lower risk per unit of exposure, or whether any indi- vidual smoker, no matter how intense her exposure, got her disease there or from something else. All science can say is that it ’ s reasonable to believe that widespread reductions in smoking have been and would be associated with widespread reductions in lung cancer, even though one could also rightly say that “ the science of tobacco and lung cancer is still in its infancy. ” HUMAN AND ECOLOGICAL RISK ASSESSMENT 3 provide unequivocal bene fi ts at the population level (Cox 2016; but see also Finkel 2018). With respect to speci fi c causation, we caution that we will never know, for example, whether CTE caused Aaron Hernandez to commit violent acts (Nierenberg 2017), but we also cau- tion that it would be folly to deny that reducing RHT in football and elsewhere would be plausibly likely to reduce the incidence of CTE and its grave consequences. Although the fi elds of both chemical risk assessment and evidence-based medical guidelines are beginning to converge towards reliance on systematic review protocols to assess the weight of evidence supporting causality (Sterne et al. 2016), controversies remain as to whether conclusions that drive public-health decisions should strive to weigh the evidence oblivious to the conse- quences of an erroneous conclusion (Neutra et al. 2018). This article is a companion piece to a forthcoming article in the Arizona Law Review (Fin- kel et al. 2018) that discusses the legal and policy aspects of CTE and other health/safety haz- ards in the NFL. That article concluded that OSHA de fi nitely has jurisdiction over the NFL workforce (the League ’ s fans call the employees “ players, ” but they are clearly salaried work- ers covered by the OSH Act), and that a hypothetical regulation reducing CTE risks, while politically unlikely, would likely be permissible as meeting the various evidentiary hurdles OSHA must cross in order to impose salutary and “ feasible ” controls. 6 While that article did not go into detail on the disciplinary differences that explain the widespread skepticism that RHT is a hazard suf fi ciently understood and suf fi ciently serious for OSHA regulation, this article confronts the divergence directly. However, this article does not discuss any of the possible interventions that might reduce CTE in professional football, either in terms of their likely effect on reducing RHT or in terms of the theory and evidence suggesting that any par- ticular diminution in RHT in football might affect CTE risk. As part of this article, we provide (for the fi rst time in the literature, to our knowledge) a QRA estimating a lower bound for the risk that an NFL player will develop CTE given current RHT exposures in the sport. This assessment does not profess to offer a central estimate of this risk, but the estimation of a lower bound does counter the statement of Maroon et al. (2015) that data do not exist to make such a calculation. We will show that this lower bound amply exceeds the 10 ¡ 3 (1 chance per 1000) lifetime-risk level that the U.S. Supreme Court opined was the boundary line below which a grave health risk might become something other than unambiguously “ signi fi cant ” (Industrial Union Dept. AFL-CIO v. American Petroleum Institute 1980, hereinafter referred to as “ the Benzene case ” ). A risk of 1/1000, of course, is much higher than the level (generally on the order of 1/10 5 or 1/10 6 ) that Congress has instructed the US Environmental Protection Agency (USEPA) to regard as possibly de minimus , and much higher than levels usually regarded as “ acceptable ” for involuntary risks (Fischhoff et al. 1983). The remainder of this article has four major sections: (1) a general exploration of how public health science evaluates accruing evidence for, in turn, hazard, risk, and severity; (2) a brief review of the current state of knowledge about the neurological hazards of RHT, the risk of CTE in professional football, and the severity of CTE lesions; (3) the basis for our ten- tative conclusions that public health experts in general, and OSHA regulatory scientists in particular, would look at the current CTE evidence and conclude there is reason for 6 The article ultimately recommended, however, that various “ soft law ” mechanisms would likely be more useful and construc- tive here, particularly the model of an “ enforceable partnership ” wherein OSHA, the NFL, and the players ’ union would jointly craft a code of conduct to reduce RHT. In such a model, OSHA would disclaim any ambition to write and enforce a regulation, but the private-sector parties would in turn agree that adhering to the code of conduct would constitute the employers ’ “ general duty ” under the OSHA statute and that OSHA could issue citations for failure to perform that duty. 4 A. M. FINKEL AND K. F. BIENIEK concern — but in each of the three steps of the assessment we follow these appraisals with various caveats and counterarguments; and (4) a general summary about how public health and medical/legal experts might reconcile their disparate views about the adequacy of the evidence base here. In what follows, we often try to explain features of the appraisal of CTE and RHT by drawing analogies to how the well-developed methods used in chemical risk assessment han- dle hazard identi fi cation, dose – response assessment, and severity appraisal. Such analogies may seem strained, since RHT is not a toxicant and CTE is not a consequence of DNA dam- age. But readers of this journal should appreciate that our fi eld of risk assessment has much to offer to the appraisal of certain physical stressors that may cause long-term harm. The human, animal, and mechanistic evidence linking RHT to CTE can feed into the kind of weight-of-evidence classi fi cation methods used in chemical risk assessment; more practi- cally, if voluntary or mandatory limits are ever to be set for exposure to head trauma, ana- lysts will need to develop and evaluate indices of exposure and assess their fi t to various physiologically plausible dose – response models, just as we do routinely in cancer risk assessment. How regulatory science assesses emerging evidence In the courtroom or at the bedside, interested parties must grapple both with general causa- tion (is it more likely than not that particular exposures can cause a particular disease?) and speci fi c causation (is it more likely than not that this did occur to the particular plaintiff or patient?) Public health, by contrast, is concerned with whether scienti fi cally sound reasoning can support the key premise that exposure reductions among a population will be associated with incidence reductions among that population : for this to be true, the exposure does not have to be the sole or even the proximate cause of the disease, and we certainly do not need to know how or why the exposures are linked to adverse effects. However, we believe the dif- ference in orientation goes far beyond this, and has more to do with whether and how uncer- tainties are both acknowledged and handled, as we will discuss. The evidence public health professionals consider invariably emerges from some combi- nation of toxicologic fi ndings (controlled studies on experimental animals), human evidence (ranging in ascending order of robustness from isolated case reports, to epidemiology studies 7 , to full-scale clinical trials, which obviously are rare when environmental toxicants are involved), and mechanistic evidence (e.g., in vitro studies of how a particular chemical effects its harm at the cellular level). Because this is an article about occupational risks where OSHA has primary jurisdiction, we will focus our discussion of risk assessment and science-policy practice on that agency; however, most of this discussion would apply equally to USEPA, the Food and Drug Administration (FDA), the Consumer Product Safety Com- mission (CPSC), the National Highway Traf fi c Safety Administration (NHTSA), and the other public health regulatory agencies, as they all developed their approaches to evaluating 7 There are two fundamentally complementary types of epidemiologic studies. “ Cohort studies ” compare persons exposed versus unexposed to a putative hazard, to see if the incidence of a disease is greater in the former group. “ Case-control stud- ies ” look at persons with a disease and a matched control group of healthy persons, to see if the former group is made up of persons more likely to have been exposed to the hazard. Since CTE can only be diagnosed de fi nitively at autopsy, not enough time has elapsed for any true cohort studies to have been mounted – the best epidemiologic evidence at present comes from studies like Bieniek et al. (2015) (CTE incidence in subgroups with and without prior RHT exposure). HUMAN AND ECOLOGICAL RISK ASSESSMENT 5 epidemiologic and toxicologic evidence at roughly the same time and with very similar results (Rhomberg 1997). If (and such cases are uncommon) we had direct observational evidence of a “ natural experiment ” wherein small reductions (and subsequent increases) in population exposure reliably led directly to reductions (increases) in population disease incidence (Li et al 2010), or to reductions/increases in upstream biomarkers in turn known to be causally related to disease (Rich et al. 2012), there would be little controversy about the sign and magnitude of population risk as a function of exposure. But controversy would likely still remain about the probability that any identi fi ed individual would be harmed by a given amount of expo- sure (due to interindividual variability in susceptibility; that is, the risk per unit of exposure). More importantly for this article, even absent any controversy about the magnitude of an individual ’ s risk, doubt will always remain about whether the risk will manifest itself in harm – that is indeed the very de fi nition of risk (a probability that either will or will not result in harm), just as the 0.50000 ... “ risk ” of a coin landing on “ tails ” can describe only the behavior of a large number of coin fl ips, never any speci fi c fl ip before it takes place. But even when observers from different fi elds can agree to discuss population risk, not individ- ual causation, they may place very different emphasis on the twin human faculties of observation and inference. One of us (Finkel 2009) has referred to human health risk assessment as sur- rounded by a “ fundamental conundrum ” : namely, that risks too large to tolerate are also often too small to detect reliably. Recognizing this fact helps explain why the kinds of “ proof ” sometimes demanded in clinical medicine and law are discordant with what public health and regulatory sci- ence seek. To draw an analogy, when Galileo saw four moons of Jupiter (four more than anyone else had ever known were there) circa 1610, he set in motion the development of more and more powerful telescopes through which scientists detected many more moons. But even before we sent probes to observe the Jovian satellites close at hand, we also became able to reliably con- clude that additional moons existed beyond our limits of Earthbound observation, by tracking the motions of those moons we could see and inferring that perturbations in their orbits had to be caused by other satellites we could not yet see. So public health and regulatory science are comfort- able using, even relying on, indirect methods of inference. Regulatory agencies generally call these inferences “ default assumptions, ” and ideally they express the scienti fi c consensus about how to interpret evidence in the absence of compelling (often case- or chemical-speci fi c) reasons to the contrary (NRC 1994; NRC 2008). For exam- ple, OSHA and USEPA typically require that a chemical must cause a signi fi cant excess of tumors in two different species of laboratory rodent before it will treat it as a “ presumed ani- mal carcinogen ” (USEPA 2005). Some agencies are left to their own devices as to whether to favor “ conservative ” defaults that tend to infer (greater) hazard, risk, or severity in the absence of contrary information (NRC 1994, Appendices N-1 and N-2) – but OSHA has been given explicit guidance by the Supreme Court to use “ conservative ” assumptions, “ risk- ing error on the side of overprotection rather than underprotection ” (Industrial Union Dept. AFL-CIO v. American Petroleum Institute 1980). The National Academy of Sciences has twice (NRC 1994; NRC 2008) urged USEPA and other agencies to articulate all their defaults, and to use clear and predictable logic if and when they decide to depart from a default, such as a policy that alternative evidence would need to be “ clearly superior ” to the evidence supporting the default. The NRC has also recommended strongly that agencies explicitly state their criteria for what general quantity and quality of evidence (for each of the major defaults) will likely be needed to make a “ clearly superior ” or other showing. 6 A. M. FINKEL AND K. F. BIENIEK A brief summary of the inferences OSHA (and USEPA) generally employs is as follows: Hazard identi fi cation USEPA and other agencies often focus their concern based solely on animal toxicology data, adopting the reasonable presumption (amply validated in general terms from past experi- ence) that exposures capable of producing signi fi cant excesses of disease in other mammals are likely also to do so in humans (Allen, Crump, and Shipp 1988). Although OSHA has on several occasions regulated an occupational toxicant based solely on evidence in experimen- tal animals 8 , in the case of CTE the existing evidence is largely from human experience, so this article will not further discuss toxicologic “ defaults. ” When evaluating case reports and epidemiology studies, OSHA generally follows the mainstream of scienti fi c opinion about how to evaluate such evidence in these ways, among others: For an epidemiologic result to be considered “ positive, ” the lower bound of the relative risk estimate must exceed 1.0 (at a relative risk of 1.0, there would be no difference at all between disease or injury rates in the exposed versus the unexposed subpopulations) In other words, there needs to be (usually) a less than 5% probability that any observed excess of disease among the exposed cohort (or an excess of exposure among those with the disease, in a case-control design) could have arisen due to chance when the expo- sure truly had no effect on disease (Mitts 1998). Other things being equal, a well-conducted positive epidemiology study outweighs one or more “ negative ” ones. It is, regrettably, fairly easy to conduct a human study with insuf- fi cient power (that is, too few subjects, too little incremental exposure, too little time during which exposures occurred, insuf fi cient latency between exposure and assess- ment, etc.) to detect a true positive effect. Studies that show a signi fi cant relative risk (see, e.g., the discussion infra about Bieniek et al. 2015) must still be carefully evaluated to make sure that confounding or other factors are not creating spurious results. 9 Case reports alone are infrequently the basis for an OSHA regulation, primarily because by def- inition a case series cannot itself yield a quantitative estimate of risk. To estimate risk, in addition to an estimate of the numerator (the number of exposed persons whose risk has been manifest), one also needs the denominator (the number of persons in the occupation or the number exposed to the hazard), as well as the background rate – the number of persons in the numerator who would be expected to exhibit the impairment or contract the disease in the absence of the speci fi c exposure. However, OSHA (and the courts) has deemed various case series ample for rulemaking, especially when a case cluster had appeared in a narrow geographic or occupational niche. For example, in 1977 OSHA moved quickly (nine months from initiation of rulemaking to fi nal promulgation) to set a strict exposure limit for the nematocide DBCP (dibromochloropropane) upon learning that seven workers who handled DBCP in one plant in California had lowered or 8 Several fi nal OSHA health standards, including those for methylene chloride (62 Federal Register, 1494 – 1619), methylenedi- aniline (57 Federal Register, 35,631), and ethylene oxide (49 Federal Register, 25,734), are based solely or primarily on animal bioassay data, with little or no human evidence. 9 Confounding is probably the most important fl aw affecting epidemiologic studies. However, true confounding is not as com- mon as laypeople may assume, based on how frequently this criticism is invoked. For a factor to be a true confounder, it must be associated both with exposure and with effect. For example, smoking can only create a false-positive relationship between a chemical exposure and lung cancer if smoking is associated with lung cancer (which it certainly is), and if for some reason smoking is signi fi cantly more common in those exposed to the chemical compared to those unexposed (or those more highly versus those less highly exposed). HUMAN AND ECOLOGICAL RISK ASSESSMENT 7 absent sperm counts (Bingham and Monforton 2013). 10 It took more than 10 additional years for careful epidemiologic studies to be completed on these populations, but the regulation had long since been in place by that time – so the parallel to the case series (see below) of more than one hundred former NFL players with CTE is especially instructive here. 11 One relevant lesson from the instances where case reports led to correct inferences is that even if the investigator(s) offering the reports provide no information about quantitative risk, it is often possible to reliably estimate risk based on exogenous information; the denominator can often be estimated with little addi- tional effort, and the background rate can sometimes reliably be estimated to be zero or near-zero. In these situations, case series can be (nearly) as useful as full- fl edged epidemiologic investigations. Dose – response assessment When prevailing occupational or environmental exposures to a hazard are much smaller than those observed in epidemiologic or toxicologic studies (or when proposed rulemaking has reached a point where an agency must select and justify a particular lower limit of expo- sure as appropriately “ safe ” ), it is necessary to extrapolate below the region of observation using some kind of model for dose – response. In the case of CTE, of course, the very cohort (NFL workers) whose risks are being estimated is the group from whom all the case reports are derived, so there is no need to extrapolate to lower levels of RHT – until some future date when OSHA or the NFL might be contemplating speci fi c rules or suggestions to lower the number and/or the intensity of head impacts. But in general, where extrapolation is required, agencies generally assume that carcino- genic substances exhibit approximately linear dose – responses, from the exposure level at which “ epidemic ” levels of tumor incidence are seen in the laboratory or in human subpopu- lations, down to levels perhaps 1 – 3 orders of magnitude lower. For non-carcinogenic expo- sures, public health regulatory agencies generally assume that after one fi nds a “ no observable adverse effect level ” (NOAEL) in an animal bioassay, the agency can “ adjust ” this level downward by a factor of 10 (to account for the fact that the typical human may be 10 times more sensitive to the effects of this substance than rodents are) and then by a sec- ond factor of 10 (to account for the fact that some humans may be 10 times more sensitive than the typical human) – although many scientists have urged that this “ bright line ” approach be replaced by a uni fi ed approach that models both cancer and non-cancer effects as phenomena with a continuous dose – response relationship (NRC 2008). Severity of harm Even assuming a strong and dose-related association between and exposure and an occupa- tional disease, OSHA does not have suf fi cient license to move towards rulemaking without a reasoned belief that the adverse health outcome at issue truly constitutes “ material 10 Note that the seven workers were exposed to DBCP at approximately 0.3 parts per million; the OSHA standard required employers to lower concentrations to below one part per billion. 11 In one of the most renowned examples of vindicated precautionary action outside the workplace, the FDA delayed approval of the sedative thalidomide circa 1960, largely on the basis of a very limited case report from an Australian obstetrician who delivered three babies with phocomelia (a rare constellation of birth defects) and recognized maternal ingestion of thalido- mide as the common factor. Very few U.S. babies were affected, in contrast to tens of thousands in Germany and the U.K. where the case reports were not heeded. 8 A. M. FINKEL AND K. F. BIENIEK impairment of health or functional capacity ” 12 . Occupational (and non-occupational) dis- eases all fall along a continuum of adversity, and most of the diseases OSHA has regulated to date, particularly cancer, obstructive or restrictive airway disease, and infectious hepatitis, are near the upper end of this continuum and clearly constitute “ material impairment. ” This is so even though some types of cancer can readily be cured, and even though some individ- ual cancers may be indolent, cause few symptoms until the fi nal weeks of life, or even can be found at autopsy within a person whose cause of death was wholly unrelated; in each case, OSHA would consider this tumor type a “ material impairment of health. ” In some cases, OSHA has de fi ned “ material impairment ” fairly expansively and been supported in this by the judiciary. For example, the Eleventh Circuit in 1992 upheld OSHA ’ s construal of even transient sensory irritation (e.g., itching of the eyes caused by chemical exposure) as material impairment, and further stated that even “ purely subjective responses ” could be so construed (AFL-CIO v. OSHA 1992). In general, OSHA has even construed biochemical changes that cause no symptoms as material impairment, especially when it is plausible that these are early warning signs of a latent or prodromal disease state and that future exacerbation would result in clinically salient symptomatology. OSHA ’ s rationale has always been that if it is possible that identifying a physiological change could trigger additional medical monitoring (or employee-speci fi c reduction in further exposures) that could conceivably slow the pro- gression towards overt disease, then the perturbation itself should count as material impairment. 13 Applying the public health paradigm to CTE Background information on CTE According to the 2017 Berlin Consensus Statement on Concussion in Sports by 36 neuro- scientists, “ chronic traumatic encephalopathy (CTE) ... appears to represent a distinct tauop- athy with an unknown incidence in athletic populations ” (McCrory et al. 2017). The term “ tauopathy ” refers to one of several neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), in which the protein tau (found in normal human brain) becomes abnormally aggregated and forms inclusion bodies within nerve and glial cells in the brain. The abnormal tau becomes burdened by an excess of phosphate groups (hyperphosphorylation). A frequent inclusion body containing abnormal and insoluble tau is the “ neuro fi brillary tangle, ” a lesion most often seen in the Alzheimer ’ s disease (AD) brain. 14 In CTE, these tangles accumulate in a characteristic pat- tern that is different from AD and other tauopathies. A consensus conference of 12 Section 6(b)(5) of the Occupational Safety and Health Act of 1970 (P.L. 91 – 596) gives OSHA the authority to set standards only when employees are in danger of suffering “ material impairment of health or functional capacity. ” 13 See, e.g., the newly promulgated fi nal rule for exposure to respirable crystalline silica, where OSHA determined that the mildest possible abnormality on a chest X-ray (a divided grade of “ 1/0 ” for small opacities) would be counted as silicosis, even though at this point in the disease process the employee would have no symptoms whatsoever (81 Fed. Reg. 16826, 16837 (March 25, 2016). See also 82 Fed. Reg. 2470, 2547 (Jan. 9, 2017) promulgating a fi nal rule for exposure to beryllium, in which OSHA concludes that early-stage chronic beryllium disease (CBD), an asymptomatic period during which small lesions and in fl ammation appear in the lungs, is material impairment because of “ evidence and expert testimony that early- stage CBD is a measurable change in an individual ’ s state of health that, with and sometimes without continued exposure, can progress to symptomatic disease ” (emphasis added). 14 AD also involves aggregation of hyperphosphorylated tau, but because its primary hallmark is the accumulation of fi brils of amyloid protein within plaques, it is considered a “ secondary tauopathy. ” CTE per se (when not co-existing with AD) does not display amyloid accumulation. HUMAN AND ECOLOGICAL RISK ASSESSMENT 9 neuropathologists, sponsored by the National Institutes of Health, de fi ned the pathogno- monic lesion of CTE as hyperphosphorylated tau aggregates in neurons, astrocytes, and cell processes around small vessels in an irregular pattern at the depths of the cortical sulci (McKee et al. 2016). There appear to be two different clinical presentations of CTE (Stern et al. 2013); some cases begin relatively early in life (ages 30 – 50) and involve behavioral and mood disturbances with minimal cognitive impairment, while others begin later in life and display marked cognitive impairment and often motor disturbances as well. Evidence about the RHT-CTE association The evidence supporting an association between either repetitive head trauma or football (or both) and CTE, one that suggests but does not establish causality, includes case reports, epi- demiologic studies, and mechanistic evidence and hypotheses: Case reports As of this writing, there are several case series in which survivors of NFL players have sought post-mortem brain examination. The largest of these series involves the team at Boston Uni- versity, which to date has examined 111 former players; in 110 of these cases (99%), CTE pathology was found, either in isolation or co-existing with other proteinopathies, notably beta-amyloidosis (Mez et al. 2017). This very high incidence rate (see the “ risk estimation and characterization ” discussion below) is certainly biased by the fact that only some next- of-kin were motivated to seek a pathological explanation for symptoms they were observing or experiencing. But although the case series consists preferentially of players whose symp- toms led to a (postmortem) diagnosis of CTE, the obverse relationship (a very high preva- lence of prior symptoms among those found with CTE) is also in evidence. Notably, Stern et al. examined medical records and conducted next-of-kin interviews (in a blinded fashion) regarding 36 deceased athletes with con fi rmed CTE, and found that 33 of them had either the early-onset behavior/mood variant of symptoms, or the later-onset cognitive variant (Stern et al. 2013). Of the only three subjects who were judged as asymptomati