Legal Implications of Hormesis?
State of CO-Dept. of Law
Natural Resources Section
1525 Sherman Street, 5th Floor
Denver, CO 80203
State of CO-Dept. of Law
Natural Resources Section
1525 Sherman Street, 5th Floor
Denver, CO 80203
The legal implications of hormesis depend in the first instance on the degree to which the hypothesis is accepted as scientific truth since truth is ostensibly the currency of the courts, which are the final arbiters of legal questions.
Mr. Cross's conclusion that "[t]he scientific database is sufficient to incorporate hormesis into regulation, and the quantity of data is such that hormesis could become a default assumption of risk assessment"1 seems somewhat facile given the resistance of many in the scientific community to accept hormetic responses first as being real, second as being widely generalizable, and third as being understood in any meaningful way. In a court of law, issues involving hormetic assumptions are likely to be vigorously debated in a classic "battle of the experts." In the regulatory context, the battle would need to be waged in the administrative record since a reviewing court is limited to such a record in deciding whether to invalidate a regulation.2
In the regulatory context, the legal issue can be examined from two different vantage points. Mr. Cross primarily addresses the question of what the Environmental Protection Agency (EPA) should do given existing evidence of generalized hormetic phenomenon which results in universally beneficial effects at levels below established No Observed Adverse Effects Levels (NOAELs). This is a question of science and policy as well as law. From the legal perspective, two very different scenarios could arise. First, if EPA chooses to adopt the hormesis hypothesis and incorporate it into its rulemaking decisions, would such decisions withstand legal challenge, i.e., would a court find that such decisions were arbitrary and capricious, unsupported by the record, or contrary to law, i.e., inconsistent with enabling statutes? This would depend on how strong the record is, how the hypothesis is incorporated, and the laws pursuant to which the regulation is adopted. This last question is touched upon both in Mr. Cross' article and below.
Second, if EPA rejects the hypothesis, would such rejection withstand legal challenge from the opposite viewpoint. This second question is easier to answer. In the case, Chevron v. NRDC, 3 the Supreme Court decided how much deference was to be accorded a regulatory agency. The answer was plenty. In a nutshell, where Congress has clearly and unambiguously expressed its intent, a court should invalidate a rule that is contrary to such intent (Chevron Step 1). If , on the other hand, a statute and the supporting legislative history, (i.e., conference committee reports, etc.), are subject to interpretation, the court should uphold the rule unless the agency's position is unreasonable and contrary to the statutory purpose (Chevron Step 2). The Chevron Step 2 analysis is more often applied by the courts.
This deference has been eroded under the recent pronouncements of the current activist court, and particularly in the recent decision in American Trucking v. EPA.4 In this D.C. Circuit case, the court rejected EPA's decision to rely on PM sub10 monitoring as an indicator for regulating PM sub10 emissions. Without getting into the details, suffice it to say, the court did not shy away from a fairly rigorous technical examination of the issue and arguments surrounding this issue. More notably, however, the court rejected the levels set by EPA based, not on arbitrary and capricious grounds, but on an antiquated and generally discarded "non-delegation theory."5
This decision confounds our long-held understanding of the appropriate role of the federal courts in reviewing agency decisions. As a result, it will be more difficult to predict the outcome of regulatory challenges unless and until the Supreme Court reverses on appeal. Nevertheless, even under American Trucking, Chevron remains the law of the land as it is a Supreme Court decision, and was cited by the D.C. Circuit. As the Circuit court explained, "our review is limited to 'ascertaining that the choices made by the Administrator were reasonable and supported by the record,' and does not include 'judg[ing] the merits of competing expert views."
American Trucking may have relevance to the hormesis debate for another reason. In a separate part of its decision, the court rejected EPA's revised ozone standards on more conventional legal grounds.
Petitioners presented evidence that according to them shows the health benefits of tropospheric ozone as a shield from the harmful effects of the sun's ultraviolet rays including cataracts and both melanoma and nonmelanoma skin cancers. In estimating the effects of ozone concentrations, EPA explicitly disregarded these alleged benefits.
EPA's argument was that the statute only allowed them to consider adverse effects, but the court did not buy it. Rather, it held that, "it seems bizarre that a statute [the Clean Air Act] intended to improve human health would, as EPA claimed at argument, lock the agency into looking at only one half of a substance's health effects in determining the maximum level for that substance. At oral argument even EPA counsel seemed reluctant to claim that the statute justified disregard of the beneficent effects of a pollutant bearing directly on the health symptoms that accounted for its being thought a pollutant at all (suppose, for example, a chemical that both impedes and enhances breathing, depending on the person or circumstances); he also seemed unable to distinguish that case from the one here where the chemical evidently impedes breathing but provides defense against various cancers."
Further, the court indicated that an inability to "quantify" the beneficial effects did not excuse the agency from considering them; after all, absence of quantification does not prevent the agency from considering adverse effects. Unfortunately for the poor bureaucrats at EPA, the court provided little guidance on how to incorporate consideration of beneficial effects into its standard-setting procedures.
The facts presented in the American Trucking case were somewhat dissimilar from those posed by hormesis, but the idea that the court required consideration of beneficial effects from pollutants could be cited by hormesis advocates as support for their position -though not determinative.
As Mr. Cross notes, Chlorine Chemistry Council v. EPA is probably the most relevant case law to the question posed. In that case, the Court did find that EPA abused its discretion and acted contrary to law when it insisted on incorporating a linear assumption in its final "interim" rule establishing a Maximum Contaminant Level Goal (MCLG) for Chloroform. It must be noted, however, that at issue in that case was EPA's own conclusion in its own Notice of Data Availability6 that "the chloroform dose-response should be considered nonlinear." Perhaps equally important was the Safe Drinking Water Act's directive to "use ... the best available, peer-reviewed science and supporting studies conducted in accordance with sound and objective scientific practices." Despite the scientific evidence before it and the court, EPA decided, nonetheless, to assume linearity. The court found that "[i]n promulgating a zero MCLG for chloroform EPA openly overrode the 'best available' scientific evidence, which suggested that chloroform is a threshold carcinogen."
This judicial decision is not likely to be particularly helpful in furthering the cause of hormesis because EPA is not likely to accept hormesis and then arbitrarily refuse to apply it especially after this case. A closer question would be where a party introduced specific evidence of hormetic effects with regard to a particular agent at issue and EPA, without reasonable justification, refused to accept such evidence instead assuming a linear dose-response relationship. Depending on the degree of deference the particular court was comfortable giving EPA, and the strength of the administrative record created by the agency and/or the challenging party, it is conceivable that such a party would be successful in its challenge.
The bottom line is, as the issue of hormesis does not appear to be settled in the scientific community, it is unlikely that the court would find EPA guilty of abusing its discretion if the agency were to reserve judgment or reject the hypothesis outright at this stage of its evolution. However, under American Trucking, it might find that EPA abused its discretion if hormetic effects were brought to the agency's attention and completely ignored.
Mr. Cross speculates that hormesis could result in more stringent carcinogenic standards due essentially to the increased steepness of the theoretical curve that represents a hormetic model. The steep hormetic curve, according to Mr. Cross, reflects greater risk reduction per increment of increased control of a toxic substance at least as far as the tipping point, (i.e., the point at which greater exposure means greater risk). Greater risk reduction could then justify greater regulatory costs under a cost benefit analysis. He further maintains that "[t]he same analysis applies under a significant risk standard so long as both the current exposure and the post-regulation exposure are greater than the "tipping point." Although an ironic observation, this scenario is not likely to be played out in the real world.
As discussed in the Cross article, statutes prescribe standards based on reasonable or acceptable risks. Regulatory programs may include either a statutory, regulatory or judicial gloss on cost/benefit analysis, but they do not provide for such analysis in a vacuum. If current statutes do include cost-benefit analysis, either explicitly or implicitly, they tend to require regulation unless costs outweigh benefits; they do not require regulation where benefits outweigh costs. This would not change under regulatory reform bills that have been introduced in recent years, despite their increased emphasis on cost/benefit analysis for environmental and health safety laws. For the scenario posed by Mr. Cross to transpire, the statutes themselves would need to be revised to eliminate the basic premise that regulation below the NOAEL, or 1.0 in Figure 3, is not required.
That being the case, it is difficult to see how hormesis theory would in reality drive lower standards for carcinogens. Rather, if EPA accepts the hormesis hypothesis, it will necessarily be concluding that there is a threshold under which no adverse effects, i.e., cancer, would be expected. Such an acknowledgment, it would appear, should drive the agency to find such a threshold, and presumably apply its "margin of exposure" methodology. Such modeled thresholds, like the thresholds for non-carcinogens are likely to be far less conservative than a modeled 10 -4 to 10 -6 risk level. Thus, even if a strict cost/benefit analysis would justify spending to lower levels under a hormetic model, a regulatory agency would not require reduction below the threshold which would be higher than current levels based on a linear assumption.
Mr. Cross focuses his analysis on the regulation of carcinogens. The choice is understandable as current risk assessment for carcinogens assumes linearity which is the gravamen of hormesis' complaint.7 However, potential implications of hormesis on non-carcinogens is also worth exploring. The following discussion adopts Mr. Cross' assumption, rightly or wrongly, that the hormetic effects noted in the Calabrese/Baldwin database do indeed constitute beneficial, or at least benign, effects.
Unlike carcinogens, risk assessment for non-carcinogens assumes a threshold effect. Such an approach, which is set forth in EPA's Integrated Risk Information System (IRIS), is obviously more compatible with the hormesis hypothesis than are the cancer guidelines.8 The unspoken assumption of the IRIS approach, however, is that below the established NOAEL there are no biologically significant effects from the chemical agent. Hormesis questions that assumption.
IRIS sets a "safe level," technically "an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk to deleterious effects during a lifetime." In the case of drinking water standards, EPA calls such an exposure a Reference Dose (RfD), and derives the dose by determining a NOAEL, generally based on animal studies, and applying uncertainty factors (UFs). If a NOAEL is not evident from the study, an uncertainty factor of 10 is, by default, applied to the Lowest Observed Adverse Effect Level (LOAEL) to arrive at a presumed NOAEL. To the NOAEL are applied additional 10-fold UFs to account, where appropriate, for less-than-lifetime extrapolations as well as interspecies and intraspecies variation (sensitive sub-populations).9 If the data base is particularly flawed (or particularly strong), a modifying factor can also be applied, although in practice it rarely is.
Thus, under IRIS methodology the actual reference dose is set generally 100 to 1000 -fold below the established NOAEL; yet, the data base accumulated by Calabrese/Baldwin indicates that in many instances the maximum stimulatory response occurs at a dose four - to fivefold below the NOAEL.10 The question has been raised whether society is being short-changed, or at a minimum monetary resources squandered, by protecting to levels below those at which hormesis theory would indicate either pose no threat or are actually beneficial. It is a question that is more complicated than appears at first glance. However, application of current policies, mostly dictated by statute, would preclude reliance on hormesis to justify abandonment of the IRIS approach.11
Assuming that hormesis exists, that hormetic effects are universally beneficial, and that they manifest at levels less than 10 fold below the NOAEL, what are the implications of the IRIS methodology? The answer of course is we do not know for sure; however, if you accept the assumptions and policy judgments of IRIS and the relevant environmental statutes discussed in Mr. Cross' article, application of IRIS still results in perfectly defensible practice. The confusion arises when one loses sight of the underlying purpose of IRIS and the UFs it incorporates. It must be remembered that NOAELs that are used as the starting point for IRIS calculations are almost always based on animal studies. IRIS assumes that humans may be more sensitive than any given animal model; in fact, it assumes, perhaps erroneously, that humans are 10 - fold more sensitive. If EPA is wrong, humans may miss out on hormetic effects at higher levels; if EPA is right, however, allowing exposure at levels predicted to be hormetic at 5 fold below the demonstrated NOAEL could result in adverse effects. The Calabrese/Baldwin database makes a case that a rat might benefit from a dose five - fold lower than the NOAEL derived from a rat study; but we tend not to know what the human NOAEL actually is. We have to make it up, purportedly by relying on conservative assumptions
Similarly, a less-than-lifetime study is assumed to be insufficient to identify adverse effects that could appear over a longer term.
Lastly, EPA in IRIS assumes that some individuals may be 10 fold more sensitive than others, and that the individuals in a given study can not be assumed to represent these sensitive receptors. Thus, incorporating a 5 - fold UF instead of a 10 - fold UF might enable the average individual to enjoy hormetic effects, but it could also adversely affect those most sensitive further challenging their already inferior biological defense mechanisms. Such a policy would certainly be questionable from an ethical perspective, perhaps detrimental from an economic perspective, but in any event contrary to current law which generally mandates protection of sensitive subpopulations, usually with a margin of safety.
Due to a recent and perhaps significant legal development, it would also appear that a conscious decision to essentially sacrifice protection of the few (highly sensitive) to benefit the many, may be subject to challenge, not only under the relevant environmental standard, but also under the Americans with Disability Act (ADA). In "Save Our Summers v. Washington Department of Ecology,12 a district court held that children with asthma and cystic fybrosis could challenge state air permits for open burning under the ADA. On the other hand, the court refused to grant the children a temporary restraining order because they were not likely to prevail on the merits. In the court's view, the remedy they were seeking, cessation of burning, would conflict with the Clean Air Act, and therefore would be precluded. Where enforcement of the ADA would not effect a "fundamental change" to an agency's regulatory program, however, a different result might be predicted. Again, the particular facts of a given case would determine the outcome.
Mr. Cross declines to include CERCLA in his discussion because "it generally adopts the standards of the other acts for its cleanup standards." Although CERCLA does bootstrap other promulgated requirements, such as Maximum Contaminant Levels, if they are applicable or relevant and appropriate (ARAR), such ARARs rarely control cleanup decisions. In reality, promulgated standards are seldom available for soils, and often not available for chemicals of concern at a given site. Thus, most CERCLA cleanups require some level of site-specific risk assessment which could, but do not, consider hormesis.
Under CERCLA, the legal standard is protection of human health and the environment. The meaning of this phrase is explained in EPA's implementing regulations, the National Contingency Plan (NCP): "For known or suspected carcinogens, acceptable exposure levels are generally concentration levels between 10-4 and 10-6 using information on the relationship between dose and response. The 10-6 risk level shall be used as the point of departure for determining remediation goals."
In practice, EPA in recent years has paid less attention to this "point of departure" and generally selects remedies that will prevent cancer incidents greater than 1 in 10,000.13 Under this rule, therefore, even if a threshold for a carcinogen were discovered at a dose lower than that representing a 10-4 risk level, a CERCLA site would not have to be cleaned up to that level unless it were a promulgated standard. If, however, a threshold based on a hormetic model resulted in a higher concentration being deemed safe, cleanups could become less stringent. In all likelihood, however, the NCP would be revised to accommodate a new threshold-based model for carcinogens.
For non-carcinogens, the NCP explicitly requires EPA to select remedies protective of sensitive subgroups. Therefore, as discussed above, hormesis is not likely to affect these decisions unless and until the scientific community can shed more light on intra species variation.
Mr. Cross initially, and correctly, dismisses any suggestion that government should revise its practices to ensure that the general population avails itself of the purported benefits of hormesis. It is not the role of government to "optimize" human experience. Even where regulatory agencies have made, (some might say misguided), efforts to provide for increased health benefits, (e.g., vitamin supplementation in milk and other products or fluoride in drinking water), their motivation was not to optimize, but to avoid deficiencies and resultant adverse effects. Our "minimum daily allowances" are based on avoiding adverse effects, and our recommended daily allowances are derived from average, seemingly healthy Americans; neither are based on optimizing health. Although some, especially in the nutraceutical industry, have been lobbying hard to change that orientation toward "Optimum Daily Intake," none has suggested that government should assume the responsibility of ensuring that we all incorporate the ideal amounts of herbs, vitamins and minerals in our diets. Nor would it be the government's duty to ensure that we were not deprived of low doses of dioxin or radiation or a polluter's for that matter. Therefore, beyond the potential effects described above, the hormesis hypothesis in and of itself should not have an effect on environmental regulation.14
Mr. Cross' goes on, however, to identify "tricky questions" that "remain to be answered" regarding the portion of the theoretical hormetic curve between the "tipping point" and the point at which adverse effects equal no dose conditions. Under current laws, and reasonably foreseeable laws, these questions are not so tricky.
Mr. Cross asks whether regulators should "aim for the level that corresponds with zero exposure (Eo) or should they aim for the bottom of the curve (Et)." Under current law, as discussed above, elimination of excess risks (i.e., risks in addition to those that would exist regardless of the presence of the regulated chemical) below "none" is not required. Therefore, the objective would never be set at Et or Em for that matter. Furthermore, exposures above Et or above Em and below Eo would never be considered "unsafe" how could they be if they posed less risk than no exposure at all?
Whether these laws should be changed to create Em as the objective is purely an academic question because the chances of the business lobby allowing such a change are nonexistent. Thirty-some years of environmental regulation has conclusively demonstrated that the cost/benefit ratio between cleanup costs and risk reduction flattens considerably the lower one goes. Companies are not going to accept these significant additional costs to make individuals healthier than they would have been had the pollution never occurred. Furthermore, from a scientific standpoint, the regulatory community is having a hard enough time establishing a strong basis for NOAEL determinations without worrying about fixing the tipping point for each chemical (the 4 to 5 fold below the NOAEL being more of a guideline than a rule). In addition, if regulators are truly unconvinced, as Mr. Cross suggests, that our NOAELs are protective, we should slap on another UF or enlarge the existing default values regardless of whether hormesis is real or imagined.
The most confusing portion of the Cross article is the discussion on "risk cups" perhaps because the assumptions are not stated. For example, it is not clear why "the risk cup actually makes little logical sense under linear risk extrapolation models, [but] it is a key step toward regulating with hormesis in mind;" why "[r]ecognition of hormesis might spark reconsideration of feasibility analysis and source-specific emission standards and replacement with an ambient risk cup;" why "the theory of hormesis would promote consideration of such an alternative;" or why "the recognition of hormesis could offer an incremental step in the right direction."
Under the current unreasonable risk-type standard, "a product or industry at least theoretically might be banned, if their overall risks exceeded their overall benefits" regardless of whether hormesis were recognized. It is not clear why recognition of hormesis would empower federal agencies or convince Congress to adopt such an anti-corporate approach when hormesis, as posited in the Cross article, if anything suggests that chemicals pose less of a risk at low doses than we suppose.
As to the application of hormesis to a risk cup idea, presumably issues identical to those discussed above would be relevant, i.e., whether acceptable ambient risks would be set using linear or non-linear assumptions for carcinogens or "margin of exposure" methodology, or a methodology for non-carcinogens less conservative than IRIS.
The conclusion of this response is directly contrary to that of Mr. Cross. It is not clear at all that "[c]onsideration of hormetic effects could distinctly enhance the benefits of public health regulation and might even provide the sort of dramatic change that could provoke a legislative breakthrough or other action to restructure environmental regulation and offer additional benefits." The most interesting implications of the exploration of hormesis at this stage are scientific and not legal or regulatory. At a minimum, a serious pursuit of this line of inquiry would presumably require considerable more experimentation with low doses. Additional knowledge regarding effects at doses more likely to be experienced in the real world can only benefit the public. If such doses are found not to cause adverse effects, the costs of compliance may go down. On the other hand, a greater understanding of the mechanisms of action, i.e., adaptive responses, could shed much needed light on questions of multiple chemical interactions, and lead to a conclusion that, given the myriad of exposures to which we are exposed on a day to day basis, even more stringent regulation is called for.
Once these and other scientific questions are asked and answered, the conclusions can with little trouble be incorporated into existing legal and regulatory frameworks.
1 Cross, Frank B. "Incorporating Hormesis in Risk Regulation," 30 Environ. Law Rptr 10778, 10780.
2 In the context of tort litigation, the first question would be whether evidence of hormesis would be admissible. The admissibility of scientific evidence is a controversial and confusing legal issue. The hypothesis would likely satisfy the "Daubert Rule," which defines when scientific evidence satisfies certain minimum credibility threshold requirements. This Rule, adopted by the United States Supreme Court, essentially allows a court to accept scientific evidence where it is relevant and reliable. It expressly rejected a previous test, which had been irregularly applied in federal courts, which required that the testimony or evidence be "generally accepted" in the scientific community. This more modern rule may increase the chances that evidence of hormesis could be considered in litigation. Whether it would carry the day would depend largely on the effectiveness of the expert witnesses brought in to testify and the specific data they could muster to support their views.
3 467 U.S. 837 (1984).
4 175 F.3d 1027 (D.C. Cir. 1999).
5 This doctrine is generally associated with the Schechter Poultry, 295 U.S. 495 (1935), in which the Supreme Court invalidated a statute because it did not provide an "intelligible principle" upon which the agency was to rely in promulgating regulations. Although never expressly overruled, courts for the past several decades have declined to apply it, and it was thought to be essentially dead-letter law. American Trucking, however, sites the case with approval. Interestingly in the dissent Judge Tatel not only criticizes the majority decision, ("the court ignores the last half-century of Supreme court nondelegation jurisprudence, apparently viewing these permissive precedents as mere exceptions to the rule laid down sixty-four years ago in [Schechter Poultry]"); but also points out that the petitioners' complaints with the rule "relate to whether the [National Ambient Air Quality Standards] are arbitrary and capricious" not whether Congress has articulated "intelligible principles."
6 62 Fed. Reg. 59,388 (1997), and 63 Fed. Reg. 15,674 (1998).
7 It should be noted that carcinogen risk assessment is not the only area in which EPA assumes no threshold. This assumption is also utilized by EPA in setting NAAQS for certain chemicals, including ozone and particulate matter.
8 U.S.EPA, Proposed Guidelines for Carcinogen Risk Assessment, 61 Fed. Reg. 17960 (Apr. 23, 1996).
9 Somewhat different methodology is used to derive Reference Concentrations for air-born contaminants; however, the analysis is similar.
10 Calabrese, E.J. and Baldwin, L.A. "Reevaluation of the Fundamental Dose-Response Relationship," BioScience, 49(9):725-732; September 1999.
11 Other criticisms of IRIS, such as the prevalent reliance on one critical study upon which to base a regulatory standard, and default application of a 10 - fold LOAEL to NOAEL UF, are beyond the scope of this paper.
12 No. CS99-269-RHW, September 14, 2000.
13 See e.g., EPA's Role of the Baseline Risk Assessment in Superfund Remedy Selection Decisions, OSWER 9355.0-30, April 22, 1991.
14 "Source-specific feasibility standards" generally should
not be affected any more than other types of
regulation discussed above because such technology driven
standards presuppose that there is risk at levels above those
effected by implementation of the technology. In other
words, companies are not expected to reduce emissions
unless such emissions are deemed harmful., even if the risks
are not quantified. Thus, if adoption of the hormetic
paradigm results in higher standards, those standards would drive,
or perhaps replace, technology-driven standards. To
the extent that it is generally preferable to base standards
on risk rather than feasibility of technology, hormesis
could indeed "provoke a desirable change in the use of
feasibility standards." Effects beyond this, however, are not clear.
Regulation of pesticides to avoid hormetic effects in
insect populations and other such environmental issues
pose interesting questions, but they are beyond the scope of