Haloacetic Acid Technical Info.
Potential Health Effects from Haloacetic Acids
Chloroform and Chlorite
(EPA References - 5103/5014 HomeHaloacetic Acids)
Harmful Effects
According to the EPA, there may be an increased risk of cancer as a result
of long-term consumption of water with levels of HAA’s that exceed the MCL
(Maximum Contaminant Level) set by the EPA. (The MCL for HAA’s 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 HAA’s on the whole than many of the Trihalomethanes
(particularly chloroform), and there is more information available on
certain HAA’s (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.
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. 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, and a single dose of dibromoacetic acid (DBAA) or
multiple doses of DCAA have caused testicular damage in rats.
Though the main route of human exposure to HAA’s 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.
Dose-Response
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 HAA’s, 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. 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.
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.
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. 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. 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. 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. DBAA is also excreted rapidly and does not appear to
bioaccumulate. 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. 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. 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. Since HAA’s 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.
Molecular Mechanism of Action
Results are mixed with regards to the molecular mechanisms of action for
HAA’s. For example, results of most in vitro tests with DCAA (with or
without metabolic activation) have been negative or ambiguous. In vivo
studies haven’t 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
isn’t 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.
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.