A Little Light Weekend Reading – The National Academy of Science’s TCE Report

In its introduction, the NAS committee strikes a note of urgency with regard to assessing TCE risks:

The committee found that the evidence on carcinogenic risk and other health hazards from exposure to trichloroethylene has strengthened since 2001. Hundreds of waste sites in the United States are contaminated with trichloroethylene, and it is well documented that individuals in many communities are exposed to the chemical, with associated health risks. Thus, the committee recommends that federal agencies finalize their risk assessment with currently available data so that risk management decisions can be made expeditiously.

One of the controversial elements of EPA's 2001 risk assessment was the hazard identification, or the compilation of evidence used to determine if TCE posed a threat to human health. EPA relied on a meta-analysis of the available epidemiological studies, prepared by Daniel Wartenberg at Rutgers. Another meta-analysis had been presented to the NAS in 2005 (which looks to have been industry-funded based on the authorship). The NAS concluded that both had limitations, that neither should be used in the TCE risk assessment, and recommended preparing a new meta-analysis of the epidemiological data. You'll probably hear opinions to the contrary, but this may not be terribly significant for the risk assessment. The NAS seemed persuaded by the evidence that TCE poses a kidney cancer risk (see below).

The NAS committee noted that TCE has been shown to be toxic to the kidneys, both in laboratory animal studies and in humans. It concluded that TCE was a potential kidney carcinogen, based on laboratory animal studies, mechanistic studies of the metabolism of TCE, and epidemiological studies. It observed that kidney cancer in animals was preceded by kidney toxicity and more pronounced in male rats than female rats, and absent in mice. TCE requires metabolic activation to produce kidney cancer both in animals and humans (in other words, a metabolite of TCE is the carcinogenic agent). You may hear arguments that the studies in animals are not compelling, because the cancer in rats is an artifact of aged male rats, and that the metabolic pathways in rats are not significant in humans - suggesting TCE is not a human kidney cancer risk. Again, it sounds as if the NAS seemed persuaded by the evidence that TCE poses a kidney cancer risk. The details may be in the body of the report (this commentary is drawn from the executive summary).

The NAS committee noted that susceptibility to kidney cancer risk may be related to variability in levels of a key enzyme that metabolizes TCE, and with the occurrence of mutations in the von Hippel-Landau (VHL) tumor suppressor gene. Could these factors point to a population that is potentially sensitive to kidney cancer risks from TCE exposure? The NAS doesn't say that in so many words, but other investigators (here and here) suggest that might be the case.

The NAS committee concluded that humans were much less susceptible to liver and lung cancer from TCE exposure, compared with laboratory animals, due to the differences in metabolism between the species. It observed that animal and epidemiological studies suggested that TCE may be associated with reproductive and developmental toxicity, including male and female infertility and cardiac malformations, though the relevance of some of animal study results to humans was unclear. The NAS committee also noted mixed results (in other words, some positive, some negative) in epidemiological studies of congenital defects in heart valves in communities exposed to TCE, but that the heart valve defects observed were the same in laboratory animal and the epidemiological studies.

Susceptibility to TCE toxicity was a major issue in EPA's TCE risk assessment. For example, the NAS committee observed that several factors can contribute to an individual’s susceptibility to the toxic effects of TCE, including disease states and differences in the expression of enzymes involved in TCE metabolism. These include conditions such as alcoholism, obesity, and diabetes, which are known to induce the expression of the CYP2E1 enzyme; that's the oxidative enzyme primarily responsible for converting TCE to toxic metabolites. While there are methods for addressing variability in populations in a risk assessment, it's clear we still don't understand susceptibility very well yet. Regardless of the method selected to quantify the risk from TCE, and develop cleanup levels for it, there will always need to be the awareness that these levels may not be protective for a certain portion of an exposed population. However, it's an open question of how sizeable that portion might be. For example, CDC reports that 33 states show rates of obesity in the population ranging from 20-24 percent, with 9 states with rates over 25 percent. In addition, CDC reports that the nationwide incidence of diabetes is 7 percent in individuals of all ages.

One last thing: The NAS committee stated that none of the existing epidemiologic data is suitable as a primary means of quantifying cancer risks, which should put to rest the "TCE is 40-times more carcinogenic than previously believed" meme that was running around the internets earlier this year.

My sense of the overall story so far:

As always there are uncertainties in the evidence, however the principal health concern with TCE may be kidney cancer. Other concerns include possible developmental toxic effects, particularly cardiac valve defects. The risk of adverse effects may be more significant for susceptible populations; some of the factors contributing to potential susceptibility, such as obesity and diabetes, are relatively common in the U.S. population. TCE exposures are widespread across the U.S., and the NAS is encouraging agencies to finish up the TCE risk assessment so that risk management decisions can be made expeditiously.

More on TCE later. This was just from the executive summary.