Standards of Proof, Presumptions and Defaults: Tools for Thinking about Environmental Health

Protections

Carl F. Cranor

Distinguished Professor of Philosophy Faculty Member, Environmental Toxicology

Graduate Program, University of California, Riverside

Standards of Proof

• Standards of proof, presumptions, and defaults provide models for different approaches to scientific evidence in environmental health decisions.

• Abstract structural similarities:

• A body of similarities, e.g., empirical evidence,

• Social, legal or scientific values as part of a rationale, then

• Specified (or vague) standards of evidence for departing from the background views.

Standards of Proof: Examples

• A criminal defendant must be found

guilty beyond a reasonable doubt. [A non-rebuttable enforceable norm].

• A defendant’s interests of “transcending value”—avoiding loss of liberty, isolation, and social condemnation—may not be changed without overwhelming evidence in order to limit mistakes. (Speiser v. Randall, 1958)

Standards of Proof: Examples

• A tort or personal injury law defendant, alleged to have injured another, may not have his/her legal status changed to pay compensation without the balance of evidence favoring liability. [A non-rebuttable enforceable norm].

Standards of Proof: Examples

• Unusually a civil defendant may be held

accountable when harm results from disfavored behavior (short of criminal conduct), e.g., “fraud,” deception”, or “undue influence.”

• This must be supported by clear and convincing (or highly probable) evidence. [A non-rebuttable enforceable norm].

Legal Presumptions

• Legal presumptions are rules for [determining]/inferring further facts from previously established facts. (Prosser, 1984, 240; McCormick,1984, 966)

• Examples: A child under the age of 7 is non-rebuttably presumed to be unable to commit a felony. (McCormick, 966)

• Goods damaged in transit conveyed by several carriers are presumed to have been damaged by the last carrier [rebuttable]. (Prosser, 240)

Legal Presumptions: Rationales

• Fairness: to correct an imbalance from one party’s superior access to evidence. (McCormick,968)

• Legal/social policy inclines courts to benefit one party or handicap another. (McCormick, 969)

• Commonly, presumptions favor probabilities of an inference.

• A letter properly addressed, stamped, and mailed is presumed to have been delivered. (McCormick, 969)

• When violent death has occurred and suicide or other cause is not clear, the presumption is against suicide. (McCormick, 972-73)

Legal Presumptions

• Legal or scientific presumptions and default approaches in regulatory science are rebuttable norms.

• Typically they are

• Based on empirical evidence and/or important scientific or social values, they identify some favored position or status quo—e.g., protection of children, linear extrapolations at low doses—or disfavored view—e.g., toxicants having related features should be treated similarly.

• There are provisions for departing from the status quo.

Defaults in Regulatory Science: NAS Recommendations

• Should be consistent with evolving science. (NRC, 2008, 184)

• Have a clear standard to justify the plausibility of the

default for a wide array of circumstances. (NRC, 2008, 184, 186)

• Have clear scientific standards for identifying when a

departure is appropriate. (NRC, 2008, 184, 191)

• Determine when evidence supporting an alternative

assumption is robust enough to depart from the default. (NRC, 2008, 184, 186)

NAS: Defaults Are Efficient

• They make explicit the existing assumptions or develop new

assumptions to address missing defaults. (NRC, 2008,186)

• They avoid “full ad hoc examination of data and the spectrum of inferences they may support without being selective or contrasting them with the default to reflect on their plausibility.” (NRC, 2008, 176)

• They [provide important starting places, help to clarify discussions], avoid ad hoc choices, provide predictable and consistent risk assessment structures and a basis for the public assessment of its actions. (NRC, 2008, 176, 184)

Some EPA Defaults

• The 1996 Food Quality Protection Act (FQPA) mandates the use of a safety factor of 10 unless EPA has sufficient evidence to determine that a different value is more appropriate [Sec. 408(b)(2)(c)].; NRC, 2008, 187)

Some EPA Defaults

• “When cancer effects … in … humans are attributed to … to an agent, the default … is that … data are predictive of cancer in … other exposed human population[s].” (EPA 2005a, A-2); NRC,2008, 179)

• “When cancer effects are not found in an exposed human

population, this … is not generally sufficient to conclude that the agent poses no carcinogenic hazard to this or other populations of potentially exposed humans, including susceptible subpopulations or life stages.” (EPA 2005a, p. A-2; NRC, 2008, 179)

Some EPA Defaults • Extrapolation from animals to humans

• “Positive effects in animal cancer studies indicate that the agent under study can have carcinogenic potential in humans.” (EPA 2005a, p. A-3; NRC, 2008, 179)

• “When cancer effects are not found in [two or more appropriate] well-conducted animal cancer studies and other information does not support the carcinogenic potential of the agent, … the agent is not likely to possess human carcinogenic potential, in the absence of [countervailing] human data” (EPA 2005a, p A-4; NRC, 2008,

179).

Some EPA Defaults

• Extrapolation of metabolic pathways

• “There is a similarity of the basic pathways of metabolism and the occurrence of metabolites in tissues in regard to the species-to-species extrapolation of cancer hazard and risk.” (EPA 2005a, p. A-6); NRC, 2009, 179)

• For oral exposure, “a human equivalent dose for adults is estimated from data on another species by … a scaling factor [of] body weight to the 3/4 power. [This] is [also] slightly more protective than using children’s body weight” (EPA 2005a, p. A-7; NRC, 2008, 179).

Some EPA Defaults

• “When the weight of evidence evaluation of all available data are insufficient to establish the mode of action for a tumor site and when scientifically plausible based on the available data, linear extrapolation is used as a [health-protective] default approach.” (EPA 2005a, p. 3-21; NRC, 2008, 179)

• Nonlinear approaches generally should not be used in cases where the mode of action has not been ascertained. (EPA 2005a, p. 3-21; NRC, 2008, 179)

One Generic Idea

• Identify some disfavored toxicity status based on accumulated evidence with a presumption for finding similar toxic effects (that may vary in potency) to identify other toxicants in a relevant class.

• “Anchor” substances that exhibit toxicity with certain mechanistic properties. (Zeise, 2017)

• Apply to other compounds exhibiting similar mechanistic

properties to estimate their toxicity and avoid human harm.

Example of a Toxicological Presumption

• Scrutinize all epoxides or epoxide-forming chemicals

for toxicity.

• Aim: to prevent such exposures or to reduce existing exposures, unless there is evidence to contrary that there are no unreasonable risks to human health.

Example of a a Toxicological Presumption • 12 high volume epoxide-forming chemicals are

alkylating agents that react with nucleophilic sites on DNA, damage them, producing mutagens and likely causing cancer.

• “[T]he three-membered ring structure [makes] epoxides … reactive molecules.” (Melnick, 2002)

• “Reducing occupational and environmental exposures to these chemicals will certainly reduce human cancer risks.” (Melnick, 2002)

Create a Default for Epoxides and Epoxide-forming Substances

• Substantial, but not complete, data on epoxides.

• Many are carcinogenic in animals.

• Numerous DNA adducts produced by this class of substances have been identified.

• “The types of mutations detected in epoxide-induced tumors are consistent with the types of DNA adducts formed by these agents.” (Melnick, 2002)

• Plausible default: Products that are epoxides or epoxide-forming substances are presumed to cause cancer in humans and people should not be exposed unless there is strong countervailing evidence.

Role of Mechanistic Evidence in Upgrading Epoxides

2002 Known Human Carcinogens benzene ethylene oxide vinyl chloride Probable HCs: glycidol [RAHC] styrene oxide [RAHC] Possible HCs or lower: acrylonitrile chloroprene Isoprene styrene vinyl bromide, vinyl fluoride, ethylene (not classified)

Post-Melnick article (2002) Known Human Carcinogens benzene ethylene oxide vinyl chloride Probable HCs: glycidol styrene oxide, vinyl bromide, vinyl fluoride, Possible HCs or lower: acrylonitrile [RAHC] chloroprene [RAHC] Isoprene [RAHC] styrene [RAHC] ethylene (not classified)

Second Scientific Presumption: Toxicity Equivalent Factors

• Toxicity equivalent factors (TEFs) facilitate the

estimated toxicity of related chemicals that induce the aryl-hydrocarbon (Ah) receptor.

• Example substances: • 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD),

• Related chlorinated and brominated dibenzo-p- dioxins, dibenzofurans, and planar biphenyls.

• There is a TEF formula for generalizing between substances. (Faustman, Omen, 2001)

Cautionary Notes for New Science: Identifying Genotoxic Carcinogens

• Some substances are non-mutagenic in numerous cell culture assays, but positive in animal studies:

•2-nitrotoluene (2NL) a probable human carcinogen (IARC) and mutagenic (EU Commission)

• Metabolism seems quite important in activating 2NL. (Eastmond,

2012)

•Clororprene—an IARC possible carcinogen; an NTP RAHC.

• It is positive for mutagenicity in some studies; negative in many, yet is an epoxide-forming substance that is structurally similar to 1-3 butadiene and isoprene (should be part of Melnick’s list) . (Eastmond, 2012)

Cautionary notes for New Science: Identifying Genotoxic Carcinogens

• Some substances are mutagenic in numerous cell culture assays, but negative for mutagenicity in animal studies:

• Captan was once classified as a probable human carcinogen (EPA) and mutagenic.

• Despite positive mutagenicity results, “captan was determined to act through a non-genotoxic mechanism based on ... high reactivity and anticipated short lifetime of captan and thiophosgene under physiological conditions, combined with lack of observed genotoxic effects in vivo both systemically and in the target organ” (Eastmond, 2012)

For Premarket Review

Find toxicity triggers for the earliest evidence of hazards and provide extra scrutiny before the public is exposed:

Good structure-activity protein and DNA alerts, e.g.,

PBDEs, epoxides.

Substances that are strongly mutagenic according to certain quick test batteries (must be done carefully).

Binding to certain cellular receptors (e.g., Ah receptor). (Cranor, 2001, 2003)

Congress Passed the “Old” Toxic Substances Control Act (1976)

• The Council on Environmental Quality found (1971) that

• toxic substances were entering the environment,

• they could have severe effects,

• existing legal authorities were inadequate to address toxicity at the point of manufacture, and

• new legal authority was needed to address these issues (PCBs a major concern) (CEQ, Toxic Substances, 1971) .

Under “Old” TSCA(1976) We lived in a Postmarket World

• Substances entered commerce with little or no careful review for toxicity.

• They remained in commerce until an overwhelming scientific case established their toxicity to reduce risks.

• The focus usually was how to make postmarket risk assessment faster while retaining accuracy.

Partial Postmarket Risk Assessments were Glacial

Substances in EPA’s Integrated Risk Information System: Trichloroethylene (TCE)—known human carcinogen, also causes Parkinson’s disease (20+ years).

Dioxin—known human carcinogen (20+).

Perchloroethylene—probable human carcinogen; neurotoxicant (13+).

Formaldehyde—known human carcinogen, including leukemia (11+).

Naphthalene—probable human carcinogen (9+) (GAO, 2005).

Sluggish Postmarket Protections Are Unjust: Hairdresser Sandy Guest’s Death

• She used Brazilian Blowout—“loaded with formaldehyde”—and died of leukemia (55) . (Morris, 2015)

• 1981-2011: 17 studies revealed formaldehyde caused various cancers—nasopharyngeal, sinonasal, and myeloid—but still there are few or no EPA protections.

• Industry resistance and slow EPA review likely led to Guest’s death.

Oxford University Press, 2017

“We should no longer be limited to repairing the damage after it has been done [Torts]; nor should we continue to allow the entire population or the entire environment to be used as a laboratory [postmarket].” (CEQ Toxic Substances, 1971)

This is precisely where we remain 46 years later.

The Council on Environmental Quality’s Hopes Have Been Dashed

“New” TSCA Promises Better Protection of the Public

• The EPA “must make an affirmative finding on the safety of a new chemical or significant new use of an existing chemical before it is allowed into the marketplace.” (EPA, 2016)

• It formally seeks to protect children, highly exposed workers, pregnant women, and the elderly from toxicants, both premarket and postmarket.

• It also has “rigorous” postmarket review deadlines.

Developing Children Are Especially

Vulnerable to Toxicants

• Have greater exposures per body weight.

• Are more susceptible to toxicants.

• Have lesser defenses.

• Have a longer lifespan for diseases to develop.

• Some adverse effects are irreversible.

Twenty-First Century Science Holds Hope for Faster Protection of the Public

• Twenty-first Century Science points to evidence that

might accurately protect susceptible subpopulations before exposures and more quickly remove existing toxicants from commerce.

• What scientific defaults, modeled on the above examples, might lead to better and more efficient use of scientific studies to provide the protections?

Will “New” TSCA and 21st Century Science Better Protect the Public?

• Will the evidentiary bar for new substances be too low?

• The EPA’s approval of 600 new substances in a few months is not reassuring.

• Will the evidentiary bar for existing substances

be too high?

• EPA’s failure to ban chlorpyrifos with an overwhelming body of data and without support of its scientists also does not bode well for protecting susceptible subpopulations.

Will “New” TSCA and 21st Century Science Better Protect the Public?

• Public health protections in premarket and postmarket assessments depends upon how they are administered.

Thank you