June 14, 2018 Articles

Understanding the Uncertainty with Unregulated Contaminants

Human health risk is the most important factor but is often the most difficult to understand and time-consuming to establish.

By Catherine Boston and Adam H. Love – June 14, 2018

Given the vast number of chemicals in the stream of commerce today, it is not feasible to provide health-based exposure limits for all of them. Establishing safe exposure levels for constituents of concern (COCs) involves an enormous amount of time, resources, and stakeholder considerations. The effort to develop technically defensive regulations is often unjustified for uncommon COCs or chemicals that are not suspected of posing human health risks (drinking water COCs are regulated at the federal level per the 1996 Safe Drinking Water Act and also can be regulated at the state level).

Ultimately, establishing regulations balances the frequency of occurrence (size of population potentially impacted), time and cost constraints, and level of human health risk. While all of these factors are contemplated when establishing regulations, the degree of human health risk is the most important factor to consider. Unfortunately, human health risk is often the most difficult to understand and time-consuming to establish.

Understanding Human Health Risk
Determining human health risk is often the bottleneck in establishing regulation due to its complexity and associated uncertainty.

Three questions guide the evaluation of risk. The process of understanding human health risk requires toxicologists, risk assessors, and regulators to quantify risk by answering three fundamental questions:

  • How much of the COC is present in the environmental media of concern?
  • How much contact (exposure) does a receptor have with the COC in various exposure media?
  • And, finally, how inherently toxic is the COC?

Determining if a COC poses an unacceptable level of human health risk becomes more difficult when, as with most unregulated chemicals, it is difficult to answer one or more of the three fundamental questions or when there are multiple COCs.

Human health risk assessments involve many components. The components of a human health risk assessment (HHRA) are illustrated in figure 1.

Figure 1. Human Health Risk Assessment

Understanding the role of the different components of HHRA is critical for toxicologists and human health risk assessors to evaluate potential exposure, risk, and associated uncertainty.


  • Source: Without a source of COCs, no exposure is possible. The source is the starting point for all subsequent components of exposure assessments. Examples of sources include leachates from landfills, leaking storage tanks, and releases from industrial facilities.
  • Media: COCs stemming from the source can migrate to various exposure media, including soil, groundwater, and indoor air. Different COCs have different inherent properties that enable them to travel differently depending on the media they are in, so it is critical to understand the various media they are in and the fate and transport of COCs in each medium.
  • Contact: For exposure to occur, a receptor must contact the media containing COCs. Contact can occur via dermal contact, ingestion, inhalation, or infant ingestion of contaminated breast milk. In some cases, although drinking water may be the exposure media of primary concern, exposure can also occur via additional pathways, such as bathing with water (dermal contact and inhalation of water vapor).
  • Absorbed Dose: Absorbed dose is the amount of the chemical that enters the body as a result of contact with COCs. Although dermal contact may have occurred, some properties of certain COCs may not allow them to penetrate the skin, and therefore the absorbed dose may be negligible.
  • Effective Dose: While the absorbed dose allows an assessment of what has actually been biologically incorporated, the effective dose is the amount of absorbed COCs that causes an adverse effect. The effective dose can vary based on individual differences in susceptibility, genetics, and a variety of other factors.
  • Altered Structure or Function: Altered structure or function is a mechanistic understanding of how the effective dose interacts with the body on the cellular level. This is often termed the toxicant’s “mechanism of action.” One example includes disruption of acetylcholine (or enzymes that break down acetylcholine)—a neurotransmitter that is vital to many body functions.
  • Adverse Health Effect: The adverse health effect is the observable outcome of the exposure to COCs.

Much of the uncertainty in an HHRA for emerging and unregulated chemicals is related to the yellow items in the components illustrated above. Specifically, toxicokinetics (rate of intake of a toxicant versus the rate of metabolism and excretion) and toxicodynamics (how the toxicant interacts with the site of action) are two areas in which large uncertainties often exist surrounding exactly how toxicants behave or are processed by the body. These concepts lead to a more complex series of questions:

  • Is it the original toxicant causing the adverse health outcome?
  • Does the body break down the toxicant?
  • In the process of breaking down the toxicant, does the body end up producing a new toxic version (metabolite)?

Understanding these dynamics becomes exponentially more complicated when—as with most toxicants—there are multiple routes of exposure and multiple adverse health outcomes.

Quantifying Human Health Risk

Risks are quantified in an HHRA via four steps:

  • Hazard identification
  • Exposure assessment
  • Dose-response assessment (toxicity)
  • Risk characterization

Hazard identification involves determining dangers. Hazard identification, the first step in the HHRA process, is where potential biological hazards are broadly identified. This step does not involve the same high level of uncertainty as the two subsequent steps, which are critical to understanding the actual risk.

Exposure assessment pinpoints dosage. The exposure-assessment step quantifies the amount of exposure that’s occurring, i.e., the dose that’s being received. In order to assess current exposures, environmental sampling can be conducted to quantify the levels of COCs in various media, coupled with the use of generalized assumptions about frequency of exposure (typically adopted from studies such as the EPA’s 2011 Exposure Factors Handbook or state-specific guidance). Exposure factors include parameters such as body weight, rates of ingestion, and days and hours present within a residence per year. For historical exposures, quantifying exposure cannot rely on current measurements but instead requires the use of modeling or forensic tools to reconstruct the extent and magnitude of COCs in exposure media and the transport pathway of each medium. Depending on which COCs are being evaluated, it may be possible to use biomarkers to quantify past exposure (for example, mercury in hair samples). Two important national exposure-related databases are the EPA’s Unregulated Contaminants Monitoring Rule (UCMR) (sampling of unregulated drinking water contaminants) and the EPA’s National Health and Nutrition Examination Survey (NHANES) (biomonitoring). These two data sets provide a snapshot of national exposures that may be of concern.

Dose-response assessments rely on animal studies. With dose-response assessments (toxicity), there is an even higher degree of uncertainty. Most toxicity studies are rooted in laboratory animal studies due to ethical limitations that forbid intentionally exposing humans to toxic substances. While data obtained from animal models is informative about toxicity, toxicological response in mice and rats may differ in important ways from human response, and therefore the data derived from such studies includes considerable uncertainty.

Toxicity can also be understood via retrospective epidemiological studies following unintentional human exposure. However, even when epidemiological studies are available, we often are unable to deconvolute much of the data that could enable determining the mechanism of action and toxicokinetics/toxicodynamics. Instead, epidemiological studies typically are only able to establish that there is a statistical correlation between exposure and health outcome, such as in the case of people who drank contaminated water and the frequency of developing cancer. However, the crux of many toxic tort cases revolves around arguments that there is, in fact, a connection between exposure to COCs and health outcome.

Risk characterization presents an estimate of risk. Risk characterization rolls up the quantitative assessments of exposure and toxicity into an estimation of risk. The risk characterization is expressed in two ways:

  • Noncancer effects, quantified through the “Hazard Index,” which is based on the ratio of the exposure level to the level believed to cause noncancer effects. Therefore, when the Hazard Index is greater than 1, the exposure level is anticipated to potentially cause noncancer adverse health effects.
  • Cancer risk, quantified through the “excess lifetime cancer risk” (ELCR) threshold, which varies depending on the regulatory regime, not to exceed one in a million (expressed as 10E-06) to one hundred in a million (expressed as 10E-04).

Due to the uncertainty in the dose-response assessment and the exposure assessment, there is considerable uncertainty in HHRAs. Additional areas of uncertainty in HHRAs can also come from variability in sampling methodology, accuracy/inaccuracy of laboratory analytical data and evaluation of detection limits, compounding of conservative assumptions, estimating risk for infants and children, and unanticipated future-use scenarios. It is critical to understand these uncertainties and to understand that in the face of uncertainty, regulators, human health risk assessors, and toxicologists adopt multiple conservative assumptions in hopes of not underestimating risk and thus exposing populations to toxicants causing harm.

Often, for industries, the lack of regulation is a more difficult risk to navigate than regulation as those potentially exposed to COCs grapple to understand what is safe. Better human health risk information is needed for these COCs in order to provide the necessary clarity to navigate key decisions regarding handling or elimination of these chemicals from industrial processes and waste streams.

In recent years, increasing public concern, the lack of clear regulation, and uncertainty in human health risk have created a fertile environment for litigation related to unregulated contaminants.

Case Study: Sulfolane
In 2009, it was discovered that sulfolane from refinery operations in the North Pole of Alaska impacted groundwater in a plume stretching three miles from the refinery, reaching over 300 homes. Sulfolane is an industrial solvent used primarily in natural gas and petroleum refining. However, no studies had been conducted to understand health effects in people exposed to this chemical.

Most of what we know about how sulfolane might affect human health comes from studies in which laboratory animals were exposed to high levels of sulfolane for up to six months. In short-term studies, laboratory animals exposed to high doses of sulfolane showed effects on the central nervous system, such as hyperactivity, convulsions, and hypothermia. In longer studies, sulfolane was shown to possibly affect the immune system and certain organs, including the liver, kidneys, and spleen. Animal studies also suggest that sulfolane at high doses can cause developmental problems in mice. In most laboratory tests with bacteria or animal cells at concentrations comparable to the Alaska site, sulfolane did not cause cancer-like changes to the cells. However, no long-term studies in animals have been conducted to determine if sulfolane might cause cancer or any other long-term health effects at the concentration relevant to the site.

Currently, the EPA’s derivation of a chronic provisional reference dose (RfD) for sulfolane includes an uncertainty factor (UF) of over 3,000. Uncertainty factors are applied to toxicological uncertainty based on the scientific derived points of departure (PODs), which can consist of a dose in laboratory settings of “no adverse health effects” (NOAEL) or the “lowest observed adverse health effect” (LOAEL). Because these PODs are determined in laboratory settings not representative of worst-case exposure scenarios in humans, toxicologists apply UFs to account for uncertainty and ensure that the levels derived are protective. For sulfolane, the EPA’s UF of 3,000 included the following protective adjustments to account for uncertainty:

  • A UF of 10 to account for interspecies extrapolation and potentially significant differences in toxiokinetics and toxicodynamics between rats and humans.
  • A UF of 3 because there is an acceptable developmental study in mice but only a screening-level one-generation reproduction study in rats.
  • A UF of 10 to account for intraspecies differences (potentially susceptible individuals).
  • A UF of 10 because a subchronic study was used; a longer-term study was not available.

Cumulative application of these uncertainties yields a 3,000-fold decrease in the POD used to derive the RfD. Sulfolane highlights the considerable uncertainty that may exist surrounding the human health risk of COCs.

At the Alaska site, the Alaska Department of Environmental Conservation proposed a cleanup level of 14 parts per billion, whereas the refinery owner argued that 362 parts per billion should be considered safe. This difference was well within the 3,000-fold UF but resulted in the difference between a large versus limited groundwater plume remedy. Due to the uncertainty surrounding the potential human health risk of sulfolane and lack of consensus on appropriate cleanup levels, the refinery in the North Pole ultimately ceased refinery operations in 2014, citing the unknown cost of the cleanup as one of the major factors leading to the facility’s closure. The refinery owner agreed to pay for 80 percent of the estimated $100 million cost to expand the city of North Pole’s water system to serve 650 impacted properties.

Mitigation Steps amid Uncertainty
The most important risk-mitigation strategy for managing unregulated chemical use is to proactively assess and understand the potential risks and magnitude of those risks. Just because a chemical is not known to be a human health risk issue now does not mean that adverse exposures are not occurring now or that there is no future risk.

Mitigation of risks includes establishing an open dialogue with regulatory agencies to stay informed about the evolution of the regulatory perspective for COCs and understanding sensitive receptors and media that affect the relevant community and stakeholders

Risk mitigation may also involve performing some preliminary assessment of potential chemical toxicity. Such preliminary assessments often use similar chemical structures (surrogate compounds) for which more health risk information is available.

Future risk mitigation may encourage operational changes that avoid releases of COCs into the environment and focus on recycling instead of discharging waste where possible. In addition, it may warrant an evaluation of supply chains and establishment of industry groups to implement open dialogue within comparable industries about operations, strategies, and technologies that limit usage of unregulated COCs.

The ultimate goal is to avoid surprise and understand the potential human health risk to stakeholders and the potential corporate liability associated with use of unregulated chemicals.


Catherine Boston is a senior geologist at Roux Associates in Woburn, Massachusetts. Adam H. Love, PhD, is with Roux Associates in Oakland, California.

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