Commentary The Dichloroacetate Dilemma: Environmental Hazard versus Therapeutic Goldmine—Both or Neither? Peter W. Stacpoole Department of Medicine, Division of Endocrinology and Metabolism, and Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida, USA b ac Kg ROund : Dichloroacetate (DCA) is known to environmental scientists as a by-product of water chlorination and as a metabolite of industrial solvents, including Superfund chemicals. In contrast, DCA is studied by clinical investigators for its therapeutic potential in several life- threatening conditions, including genetic mitochondrial diseases, pulmonary arterial hypertension, and cancer. Thus, DCA holds an almost unique position at the interface between environmental science and allopathic medicine. Objectiv : I critically reviewed laboratory and clinical pharmacological research on DCA to address questions about the current and future status of DCA in relation to human health. d iscu On : Recent information on the clinical toxicogenetics of DCA is interpreted particularly in light of its use as an investigational drug. Adverse effects from chronic DCA exposure have been identified in several target organs in animals. However, in humans, toxicity has so far been limited to reversible effects on the nervous system and liver. DCA is primarily biotransformed to glyoxylate by the bifunctional enzyme glutathione transferase zeta1 and maleylacetoacetate isomerase (GSTz1/ MAAI), which also catalyzes the penultimate step in the phenylalanine and tyrosine catabolic path- way. DCA is a suicide inhibitor of GSTz1/MAAI, which can result in delayed plasma clearance of DCA and the accumulation of potentially toxic tyrosine intermediates. Age and GSTz1/MAAI haplotype can markedly affect the toxicokinetics of DCA in humans and rodents. c Onclusi Ons : I have defined new potential avenues of research that focus on discrete human popu- lations that may be at increased health risk or that may receive increased health benefit from chronic exposure to DCA at both environmentally and clinically relevant concentrations. Key w ORds : cancer, dichloroacetate, glutathione transferase zeta, hereditary tyrosinemia, maleylacetoacetate isomerase, mitochondrial disease, peripheral neuropathy, pyruvate dehydro- genase, toxicogenetics. Environ Health Perspect 119:155–158 (2011). doi:10.1289/ehp.1002554 [Online 4 October 2010] To many readers of this journal, dichloro- acetate (DCA) has a bad reputation that is mainly the result of its association with Superfund chemicals and other halogenated hydrocarbons of ill repute (Stacpoole et al. 1998b), the findings of numerous animal stud- ies implicating DCA in a variety of moder- ate to life-threatening toxicities [International Agency for Research on Cancer (IARC) 2004], and the ubiquity of this molecule in our biosphere that makes at least some degree of chronic exposure inevitable (Ammini and Stacpoole 2003; IARC 2004). Despite these concerns, the possibility that DCA might have a positive impact on certain human popu- lations has been evident for half a century (Stacpoole 1989). Over time, DCA’s phar- macological profile has created an interesting dialectic between environmental toxicologists, who consider it to be a hazard to humans, and clinical investigators, who are pursuing its therapeutic potential. Most ironic is the grow- ing controversy over the relevance of DCA to human cancer, in which it is viewed as both a likely cause (IARC 2004) and a possible treat- ment (Michelakis et al. 2010). The DCA dilemma has been framed by three broad fields of science: epidemiological studies of populations exposed to environ- mental levels of measured by-products of water disinfection or Superfund chemicals that are precursors of DCA; mechanism- based toxicological experiments in which inbred rodent strains receive doses of DCA usually vastly higher than those to which most humans are exposed in the environ- ment; and research in which subjects are administered DCA as a drug at doses similar to those used in animal toxicological inves- tigations. Together, the data generated by such research address three questions that are at the heart of the DCA dilemma: Is DCA a significant environmental health hazard? Are certain populations at increased health risk or benefit? What are the important areas of future research that will help con- firm, modify, or reject current opinions about DCA’s impact on human health? Is DCA a significant environmental health hazard? Human populations have been exposed to DCA for generations, primar- ily by ingesting chlorinated drinking water that may contain up to 160 µg/L (Miller and Uden 1983). Thus, consuming 2 L of municipal water may result in a DCA dose of approximately 2–4 µg/kg body weight in a 70-kg human. However, studies of worldwide exposure to chlorinated drinking water in relation to human disease did not include an assessment of DCA exposure levels (Obolensky Environmental Health Perspectives • volume 119 | number 2 | February 2011 et al. 2003). Dermal absorption of DCA may occur when bathing or swimming in chlori- nated pools or upon atmospheric exposure, although there are no good estimates of the contribution of dermal absorption to tissue or plasma levels of the compound. DCA is also considered a metabolite of the degreasing agent trichloroethylene (TCE) and related solvents, most of which are released into the atmosphere (Agency for Toxic Substances and Disease Registry 1997). TCE emis- sions and contamination of surface water vary widely across the United States but cor- relate broadly with population density and provide an estimated combined median daily intake by the general population of slightly > 13 µg/day (U.S. Geological Survey 2006). Both enzymatic (Lash et al. 2000) and nonen- zymatic (Guengerich 2004) catalysis of TCE to DCA have been reported. However, the quantitative significance of either pathway is controversial (Ketcha et al. 1996; Merdink et al. 1998; Templin et al. 1995), which contributes to uncertainty about the relevance of environmental exposure levels of DCA to human health. Nevertheless, considerable weight has been given to assigning causality to the oxida- tive metabolites of TCE [see Supplemental Material, Figure 1 (doi:10.1289/ehp.1002554)] in evaluating the toxicity of DCA. Data from population-based pharmacokinetic modeling of the toxicokinetics and risk assessment of TCE and its metabolites (Chiu et al. 2009; Evans et al. 2009) indicate that TCE expo- sure has been associated with toxicity to the kidney and liver and to the nervous, immune, and reproductive systems. How much of this information is relevant to the assessment of human risk from DCA exposure? Strong evidence from case–control studies indicates Address correspondence to P.W. Stacpoole, University of Florida College of Medicine, 1600 SW Archer Rd., M2–238, P.O. Box 100226, Gainesville, FL 32610 USA. Telephone: (352) 273-9023. Fax: (352) 273-9013. E-mail: pws@ufl.edu Supplemental Material is available online (doi:10. 1289/ehp.1002554 via http://dx.doi.org/). The author thanks K. St. Croix for her editorial assistance. This work was supported in part by grants from the National Institutes of Health [R01-ES07355, R01-ES014617, and U54RR025208-01 (Clinical and Translational Science Award)]. The author declares that he has no actual or potential competing financial interests. Received 14 June 2010; accepted 4 October 2010. 155