United States: Recent Developments in Toxicology and Regulation of Environmental Chemicals

Originally posted 14 October, 2003

By Christopher P. Davis, Lorenz R. Rhomberg and David Merrill

The toxicology and regulation of chemicals in the environment are constantly evolving as newly developed scientific information settles some questions and raises others. New studies and governmental assessments of potential human health and ecological impacts from environmental exposures to chemicals are periodically debated and revised. These studies and the risk management decisions based on them drive the promulgation and revision of federal, state, and international discharge regulations, exposure standards, and cleanup requirements.

This article, prepared with substantial expert assistance from Gradient Corporation, reviews the status of a number of prominent "environmental chemicals" which (i) are of current scientific, regulatory and public interest and (ii) illustrate some recent trends in environmental toxicology and regulatory approaches. Among the issues raised by these chemicals are the toxicological relevance of high dose animal tests to low dose human exposures, appropriate risk assessment assumptions and methodology, accounting for cumulative exposure to multiple chemicals, protecting sensitive populations, and the resulting liability and economic implications of regulatory decisions often made in the context of significant scientific uncertainty. The evolving science and regulatory policy decisions also play a major role in "toxic tort" litigation based on claimed exposure to various chemicals.

Trichloroethylene (also known as trichloroethene or TCE) is an important industrial solvent, widely used as a metal degreaser, in certain adhesives, and as a chemical intermediate. It is a volatile liquid that is denser than water. Most environmental issues about TCE concern groundwater contamination from historical spills and disposal. Degradation of TCE in groundwater is slow, and certain breakdown products (e.g., vinyl chloride) may be more toxic than TCE itself. TCE plumes at waste disposal sites, and former industrial facilities constitute the country's most common subsurface environmental contamination issue. Most human exposures are via contaminated drinking water and from breathing indoor air into which vapors from groundwater have intruded through foundation cracks or from showering with TCE contaminated water. Total TCE remediation costs nationwide run into several billions of dollars.

TCE is not very toxic in short-term exposures, but concerns about its chronic toxicity following long-term exposures have been the subject of an ongoing debate for over two decades – a debate that has recently heated up based on new data and a new draft risk assessment from the U.S. EPA. TCE causes lung and liver tumors in mice and a small incidence of kidney tumors in rats. Epidemiologic studies on TCE-exposed workers have yielded mixed results; two small studies of highly exposed workers (which have been criticized on methodological grounds) found kidney cancer elevations, but several large, well-conducted studies (of aircraft and aerospace workers) showed no kidney effect nor any consistent pattern for other cancers. However, some observers argue that the studies indicate a slight, statistically non-significant increase in liver cancer rates. Recent research has improved understanding of TCE metabolism in rodents and humans and the underlying biochemical and physiological mechanisms of TCE's carcinogenicity in animals, although substantial scientific questions in these areas remain.

EPA's official assessment of TCE's potential carcinogenicity and potency was withdrawn in 1989 pending the resolution of several issues raised by the agency's reviewing Science Advisory Board (SAB), although in practice it has been used since then on an "interim provisional" basis. It was hoped that new analyses, as well as new metabolism and epidemiologic studies, would help resolve the issues. EPA presented a revised assessment in August 2001 for SAB review. Instead of naming a single value for a cancer potency "slope factor" (as has been done historically), the agency proposed a large set of alternative slope factors, each alternative based on a different study and analytical approach, and each differing sharply in the human cancer risks implied. Collectively, all of the proposed slope factors suggest that TCE should be regarded as between 2 and 65 times more potent than it had been before. The SAB issued its written review in December 2002, which requested revision, clarification, and strengthening of EPA’s analysis in several areas. The analyses in EPA's August 2001 draft have remained an area of wide scientific discussion and controversy. As a result, EPA plans to seek a National Academy of Sciences panel to review the topic, and a finalized assessment is not expected until 2006.

The uncertain scientific and regulatory status of TCE has complicated the risk management process, notably in determining site specific cleanup standards for TCE in soil and groundwater. The various EPA regulatory programs and regional offices (as well as state regulatory agencies) have each struggled with defining a policy for implementing the new TCE assessment. Several of these entities seem to be settling on automatic use of the most conservative of the available choices, despite the clear directives not to do so contained in both the EPA document and the SAB comments. The EPA draft states, "[d]epending on the characteristics of the exposed population and the exposure scenario, each risk assessment should select an appropriate slope factor from this range," but provides little guidance on how to make this choice.

This situation opens the door for affected parties to develop scientific arguments regarding which particular cancer potency value is appropriate for their particular exposure scenario, but it creates considerable uncertainty as to which of the many alternative cancer risk calculation approaches will be applied at a given site. If the worst-case potency factor is adopted, even the trace TCE concentrations found in virtually all residential indoor air and the groundwater at many sites could be deemed to present unacceptable risks. An increase in TCE-related tort litigation has already occurred and some "final" remediation decisions (even at supposedly cleaned-up sites) are being reopened. Given the widespread extent of TCE in the environment and the already high costs of remediation, these issues will be the center of ongoing controversy and debate over the next several years, and are sure to affect cleanup plans, liability assessments, transactional due diligence and brownfields projects nationwide.

Although polychlorinated biphenyls (PCBs), have been banned in the United States for over two decades, these persistent compounds continue to pose complex environmental challenges. Historically, their resistance to heat and fire made them ideal as insulating fluids in transformers and other electrical equipment and in various types of heat transfer, hydraulic, and cutting oils. PCBs also have had diverse applications that are less well known, including use in carbonless carbon paper (leading to unforeseen PCB releases from paper recycling), as plasticizers used in swimming pools, road paints, and marine paints, in adhesives, and as pesticide extenders. Over half a million tons of PCBs were produced in the United States from the 1930s through the mid-1970s. Given their historical widespread use and their persistence in the environment, PCBs continue to garner significant attention in regulatory cleanup actions and cost-allocation disputes.

PCBs have been shown to cause a wide variety of toxic effects in laboratory animals, including cancer. While PCBs are proven carcinogens in laboratory animal studies, the debate over whether PCBs cause cancer in humans – based on the interpretation of studies of humans occupationally or accidentally exposed to PCBs – remains hotly contested as are a variety of other potential human health impacts. EPA has classified PCBs as "probable human carcinogens." Assessing the toxicity and environmental fate of PCBs is particularly difficult because PCBs are not a single compound. Rather, 209 distinct PCB "congeners" exist, differing by the number and placement of from 1 to 10 chlorine atoms per molecule. Historically, the toxicity of PCBs has been based on studies of commercial mixtures of PCBs, which were marketed under the trade name Aroclor® . These commercial mixtures in turn contained different degrees of chlorination, with unique proportions of the 209 PCB congener ingredients. (For instance, the common Aroclor ® 1260 is 60% chlorinated, and contains numerous PCB congener components.) Complicating matters, biological and physical transformations in the environment tend to change the congener make-up of an original commercial mixture, such that an "environmental PCB" has a different composition than the parent material released to the environment. Consequently, while PCB toxicity is commonly assessed using studies of Aroclors, the environmental PCB may no longer reflect the mixture at the time of release.

To date, assessing the human carcinogenicity of PCBs has largely focused on "total PCBs," with the Aroclor-based toxicity studies used as the basis for the cancer potency estimate. While it is unlikely that EPA's 1996 reassessment of the carcinogenicity of PCBs (lowering the human cancer potency estimate from its prior value) will be amended any time soon, several initiatives warrant scrutiny. Given better techniques for PCB congener analysis, and more rigorous toxicity studies, the use of PCB "dioxin-like" toxicity equivalency factors (TEFs) is gaining momentum. A number of PCB congeners share similar physical structure with dioxin, giving the PCBs their so-called dioxin-like toxicity, and each congener's TEF gives the toxicologically equivalent dioxin dose for a given PCB dose. EPA's current guidance allows for the use of TEFs for PCB risk assessment when data are available on individual PCB congener exposures. This issue is potentially significant given that EPA appears poised to finalize its dioxin reassessment, recommending an even more stringent slope factor.

Thus, cleanup levels for PCBs based on their congener-by-congener dioxin-like toxicity could potentially lead to more stringent cleanup standards than are currently calculated from an analysis of the total PCB mixture. In addition, EPA is placing greater focus on the non-cancer health effects of PCBs. Combined, these two developments again place PCBs prominently on stage as chemical drivers in many environmental disputes, and potentially could re-open existing cleanup agreements or consent orders. More stringent PCB cleanup standards could also prompt further toxic tort litigation, would increase already high cleanup costs and exacerbate already contentious debates about costs and benefits of different remediation strategies.

Under the Clean Air Act Amendments of 1990, areas with poor air quality were required to add chemicals called "oxygenates" to gasoline to improve combustion and reduce volatile organic compound emissions and control smog. The most commonly used additive in such "reformulated" gasoline (RFG), is methyl tert-butyl ether (MTBE) – in 1997, 76% of RFG contained MTBE. While air quality has improved, the role of MTBE and other oxygenates in that improvement is the subject of debate. Most research, however, suggests that the air quality benefits of MTBE use are substantial.

MTBE from RFG leaks and spills has affected numerous groundwater sources, more so in states where RFG is extensively used, although the levels detected generally have been low. The primary source of MTBE in groundwater appears to be petroleum releases from leaking underground storage tanks, as well as spills and leaks from pipelines, and above-ground storage tanks. MTBE is very soluble and once released moves through soil and into groundwater more rapidly than many other chemicals, including those present in gasoline. Once in groundwater, it is slow to biodegrade, is very persistent, and is difficult to remove.

MTBE has been frequently detected in drinking water. An EPA-appointed expert panel reported that between 5% and 10% of drinking water supplies in high oxygenate-use areas show at least detectable amounts of MTBE. Nonetheless the vast majority of these are well below levels of public health concern. Due to the concern regarding groundwater pollution, and because MTBE's odor can be detected at low concentrations, the use of MTBE is being curtailed. California, for example, is phasing out the use of MTBE. While use of oxygenates in gasoline in areas failing to meet smog standards is required by the Clean Air Act, EPA is considering proposals to use other oxygenates (such as ethanol) instead of MTBE. However, substitutes all have their own environmental and health issues, and amendments to the Clean Air Act to change its oxygenate mandates have been proposed.

Much of the debate and litigation over the past few years has centered on whether MTBE is a human carcinogen. No studies have been conducted in people, but several high-dose studies have been conducted in rodents. Based on these studies, which primarily evaluated effects from inhalation, EPA concluded that MTBE could potentially cause cancer in humans at high doses. Because of uncertainties and limitations in the data, however, EPA has not estimated risk at low exposure levels.

In 1998, the International Agency for Research on Cancer (IARC), the U.S. National Toxicology Program, and California's Carcinogen Identification Committee all elected not to list MTBE as a human carcinogen. These groups noted the limited data, especially with regard to ingestion of MTBE (the means by which people would be exposed to MTBE in drinking water). As noted by a Congressional Research Service report to Congress, the evaluation of any health risks associated with the addition of MTBE to gasoline requires a comparison to the health risks associated with conventional gasoline, which contains carcinogens (e.g., benzene) and produces carcinogens when combusted (e.g., 1,3-butadiene). Meanwhile, the widespread presence of MTBE in groundwater has resulted in class action litigation in a number of states, and the costs and benefits of using MTBE versus alternative oxygenates in RFG are the subject of continuing scientific, regulatory and legislative debate.

Methylmercury (MeHg) is the most notorious and best studied of the organic mercury compounds. It is not intentionally produced in significant quantities but arises in the environment from bacterial action on inorganic mercury that has settled in aquatic sediments, primarily as a result of releases from power plants burning mercury-containing fuel and from certain industrial processes. MeHg exhibits a strong tendency to "bioaccumulate" in aquatic food chains with fish species at the top of the food chain (e.g., swordfish, tuna and shark) typically having the highest levels. Fish consumption is the primary way humans are exposed to MeHg and the regulation of acceptable mercury levels in fish continues to be a contentious topic. The presence and remediation of MeHg in aquatic sediments is a major issue at numerous sites across the United States.

Sufficient levels of MeHg alter neurological development during pregnancy. Although the effects of MeHg can occur in adults, children are more sensitive because their brains and nervous systems are still developing. In the 1950s and 1960s, children with severe neurological impairments were born to mothers who consumed MeHg containing fish in Minimata, Japan. Currently, concerns about MeHg exposure are focused on subtle neurological effects, such as delays in reaching developmental milestones (e.g., talking). Several fairly recent studies have shown adverse neurodevelopmental effects in populations that consume large amounts of fish containing MeHg (e.g., the Faroe Islands and the Amazon Basin), but another study, conducted in the Seychelles Islands, did not find any effects of fish consumption during pregnancy on neurological development. Scientists are still debating the merits and limitations of the various studies and the implications of low-level MeHg exposure.

In response to criticisms that action levels for MeHg in fish were not sufficiently protective of many pregnant women and children, FDA and EPA held a series of meetings with industry and consumer groups in July 2003, and FDA is currently conducting additional testing of tuna sold in the United States. The agencies will revisit their advisories regarding tuna fish consumption when the new data are available.

Although the health concerns for MeHg relate largely to the eating of mercury-bearing fish, the regulatory and cleanup issues focus on preventing elemental (un-methylated) mercury from getting into the environment in the first place, even though such un-methylated mercury itself is not particular toxic. This focus on reducing emissions is necessary because, once mercury enters the environment, it is difficult to remove (there are few "hot-spots" that can easily be cleaned up) and difficult to attribute to particular sources. Recent EPA regulations have limited the amount of mercury released from municipal waste, medical waste, and hazardous waste incinerators. New regulations on power plant emissions are expected by the end of 2004, and some mercury uses (e.g., in pesticides and paints) have been prohibited. The costs and feasibility of sharply reducing mercury emissions, remediating existing sediment contamination, and preventing human exposure to contaminated fish are likely to present considerable challenges.

Perchlorate is a small inorganic molecule used as a component of solid rocket fuel by the defense, aerospace, explosives and fireworks industries. Perchlorate has also been used as a pharmaceutical to treat specific thyroid disorders, and it is still intentionally used in clinical tests of thyroid function. Discharges of perchlorate have resulted in localized groundwater contamination. Concentrations in groundwater have been reported to range from 4 to 16 parts-per-billion (ppb) in the Colorado River below Lake Mead and several hundred ppb in several drinking water wells in California. Although concerns about perchlorate in groundwater are particularly strong in the Southwest, the compound has also been detected in groundwater in other parts of the United States, particularly in the vicinity of military bases and test ranges.

The key toxicological concern about perchlorate exposure is its potential effect on the thyroid gland's production of iodine-based thyroid hormones, which in turn affect a wide variety of metabolic processes and are critical for normal development in infants. Perchlorate inhibits iodine uptake by the thyroid which can decrease thyroid hormone in the blood, a condition called hypothyroidism. Hypothyroidism during pregnancy (which can result from a variety of causes) has been associated with alterations in brain development. In rodents, perchlorate exposure can also cause sustained thyroid growth, which may lead to thyroid tumors. Despite the longtime use of perchlorate as both a pharmaceutical and an industrial chemical, however, there is no evidence that perchlorate exposure is connected with thyroid tumors in humans. The developmental effects of perchlorate are currently driving regulatory action. Detailed studies conducted in pregnant rats suggest perchlorate exposure during pregnancy and shortly after birth can affect brain development. Interpretation of the study data has been questioned, however, with some scientists preferring assessments based on the more limited but more relevant human data. The human studies are contradictory, however, with some studies showing slight effects on thyroid hormone levels while others show no effect of perchlorate exposure.

U.S. EPA, using rat data, has recently proposed a perchlorate reference dose (RfD, a daily dose believed to result in no adverse effects) of 0.03 µg/kg-day, which is equivalent to a drinking water goal of 1 ppb. California EPA, using human data, has derived an alternative drinking water value in the range of 2 to 6 ppb. (Both values are below the value of 18 ppb that was previously used by EPA and many state agencies.) In response to strong technical arguments raised by other federal agencies (primarily the Department of Defense), EPA has asked for a National Academy of Sciences review of the toxicological data. This will likely push back the date of any final action on a perchlorate acceptable daily intake for another two years. However, EPA's proposed draft RfD is already driving down provisional groundwater cleanup standards in many states and is likely to have an impact on litigation.

Costs to the Department of Defense and its contractors for perchlorate remediation will vary substantially with the final cleanup level chosen, but costs in the billions are currently being discussed – a large impact in view of the scientific uncertainty about whether drinking water levels actually threaten human health. Perchlorate is also emerging as a new target for class action lawsuits, the financial impacts of which remain to be determined. Conclusion The science and toxicological analyses underlying the regulation of chemicals in the environment are continually evolving. All current assessments of chemical toxicity and risk probably should be viewed as provisional. Reaching scientific consensus on the human health risks of various environmental chemicals is a slow and often contentious process. Governmental risk assessments and regulatory standards for chemicals of concern are typically based on extrapolations from animal studies, and are intended to err on the side of protectiveness in the face of scientific uncertainty. Evolving science and risk assessments are driving changes in regulatory standards for industrial emissions, product contents and environmental cleanup, and influencing toxic tort litigation, all with significant economic implications. The recent scientific and regulatory developments summarized above for TCE, PCBs, MTBE, MeHg and perchlorate, for example, may result in more stringent cleanup standards and increased potential liabilities associated with these chemicals. Thus, it is prudent for the regulated community to be aware of (and, where appropriate, to participate in the development of) not only current regulatory standards, but also the underlying science and risk analysis.