According to the EPA, there may be an increased risk of cancer as a result of long-term consumption of water with levels of HAAs that exceed the MCL (Maximum Contaminant Level) set by the EPA (1). (The MCL for HAAs is 0.06 mg/L) Haloacetic Acids are classified by the EPA as a Group 2B cancer classification (possibly carcinogenic to humans) because there is evidence of carcinogenicity in experimental animals, but there is either no evidence or not sufficient evidence of carcinogenicity in humans. Much less is known about HAAs on the whole than many of the Trihalomethanes (particularly chloroform), and there is more information available on certain HAAs (such as dichloroacetic acid) than others (such as the brominated acetic acids). In terms of short-term human toxicity, dichloroacetic acid and trichloroacetic acid (DCAA and TCAA) can both cause severe skin and eye irritation in humans at high concentrations (2). In studies looking at longer-term toxicity, both chemicals have been shown to cause liver tumors in mice exposed to drinking water containing DCAA and TCAA (2,6). DCAA has been shown to be a neurotoxin in adult rats, more so when administered through drinking water than when administered by gavage. DCAA and TCAA have also been shown to have reproductive effects on the fetuses of rats (2), and a single dose of dibromoacetic acid (DBAA) or multiple doses of DCAA have caused testicular damage in rats (3).
Though the main route of human exposure to HAAs is through ingestion of disinfected drinking water, DCAA has been used in larger doses in an experimental setting for treatment of congenital lactic acidosis (a metabolic disorder resulting in overproduction of lactic acid). Some patients receiving this treatment have experienced a sedative effect, and there have been a few reported cases of peripheral neuropathy. However, these symptoms reversed themselves when treatment was halted (6).
It is important to note that a quantitative dose-response relationship has been established in humans for exposure to Haloacetic Acids, mainly because it is exceedingly difficult to quantify actual human doses of these compounds. Exposure is chronic, occurs in very small amounts, and can vary substantially over time. There is limited animal data available for many of the HAAs, but some data was available for DCAA. The lowest established LOAEL to date for DCAA is 12.5 mg/kg-day based on subchronic oral exposure in dogs with a critical effect of lesions observed in the testes, cerebrum, cerebellum and liver. An uncertainty factor of 3000 (taking into account human variability, extrapolation from animals to humans, the use of a LOAEL instead of a NOAEL, a less-than-lifetime study, and deficiencies in the database) resulted in a reference dose of 0.004 mg/kg-day (6). Multiple studies indicate that the incidence of liver tumors and cancer in mice and rats is dose-related, and that the multiplicity of tumors provides evidence of a dose-response relationship (6).
Absorption, Distribution, Metabolism
Haloacetic Acids, unlike Trihalomethanes, are nonvolatile. They have low dermal absorption (at low concentrations), so the main route of exposure to them is ingestion, and rapid absorption from the intestinal tract into the bloodstream has been demonstrated in studies on rats (7).
Once in the bloodstream, DCAA is distributed to the liver and muscles, and then in smaller quantities to the fat, kidney and other tissues such as the brain and testes (7). Because DCAA has been experimentally administered to humans, some information on human metabolism is available. DCAA metabolism in humans has been determined to be similar to metabolism in rodents. The primary pathway involves the dechlorination and oxidation of DCAA to form glyoxylate, oxalate, and several glycine conjugates which are all excreted in the urine. The enzyme catalyst involved is glutathione-S-transferase-zeta (7). DCAA has also been shown to inhibit its own metabolism. After five days of daily administration of DCAA to humans, the half-life increased almost eightfold on the fifth day (6). In both rats and humans almost all DCAA is excreted as metabolites through the kidneys.
Some in vitro data indicate that DBAA is metabolized in a similar manner to DCAA (5). DBAA is also excreted rapidly and does not appear to bioaccumulate (5). It is unknown if the parent compound or a metabolite is the toxic agent, and a cohesive mode of action for the toxicity of these compounds has not been clearly established.
Sites of toxicity
The main site of toxicity from long-term exposure to the chlorinated acetic acids appears to be the liver (in experimental animals). Shorter-term (higher-dose) exposures (mainly to DCAA) have demonstrated neurotoxicity in both animals and humans. Immunotoxicity in mice has been established from short-term exposure to brominated acetic acids (5). When DBAA was administered to mice in their drinking water at various concentrations, certain effects were noted that indicated the target organ was also the liver (5). Some reproductive effects in animals have also been observed following exposure to either the chlorinated or brominated acetic acids, including reduced sperm count.
Biomarkers of disease
There are studies being conducted on biomarkers of exposure to Haloacetic Acids, and it is possible to look for exposure by testing the urine. In one study, DCAA and TCAA uptake was estimated with urine samples from female human subjects. TCAA (but not DCAA) had a relatively good correlation between the amount in urine and ingestion exposure since its biological half-life is between 70 and 120 hours (8). Since HAAs have not been clearly linked to disease in humans, there are no biomarkers for HAA-related diseases in humans. In animal studies, the liver is often a site of toxicity resulting from exposure to the chlorinated acetic acids, and serum liver enzyme levels are often used an indicator of liver damage. Serum enzyme levels, however, are not an indicator of the cause of liver damage. In studies of rats administered DCAA in drinking water, testes weights have either increased or decreased with exposure, and final mean body weights have often been reduced. Dose-dependent increases in liver weights have similarly been demonstrated, but only at higher dosage levels. (7).
Molecular Mechanism of Action
Results are mixed with regards to the molecular mechanisms of action for HAAs. For example, results of most in vitro tests with DCAA (with or without metabolic activation) have been negative or ambiguous. In vivo studies havent shown any consistent pattern of positive or negative results for genotoxicity in the mouse micronucleus assay, assays for DNA strand breaks (in mouse or rat cells), or DNA adduct formation. There isnt sufficient information available on DCAA-induced liver tumors in rodents to identify a single mode of action of toxicity. There may be multiple mechanistic pathways involved that are dose-dependent or species-specific. (7).
In a study of male mice receiving different doses of TCAA, no treatment-related effects on the mutation patterns of the K- and H-ras proto-oncogenes were observed in the liver tumors, indicating that TCAA is probably a tumor promoter as opposed to a tumor initiator. In other studies, TCAA has promoted liver tumors in mice that were also treated with a tumor initiator (7).