Contaminated Water Supplies at Camp Lejeune Assessing Potential Health Effects (2009) / Chapter Skim
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3 Systemic Exposures to Volatile Organic Compounds and Factors Influencing Susceptibility to Their Effects
3 Systemic Exposures to Volatile Organic Compounds and Factors Influencing Susceptibility to Their Effects
Pages 67-89
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From page 67... ...
As noted in Chapter 2, other contaminants have been detected in the water supplies, so exposures were more complex than just VOC mixtures. However, for the purposes of this report, the review has been restricted to the primary VOC contaminants of concern.
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From page 68... ...
for PCE to 4,800 mg/L for methylene chloride. Concentrations typically found in finished drinking water in the United States range from parts per trillion to parts per billion (Moran et al.
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From page 69... ...
Thus, systemic absorption from the lungs, skin, and gastrointestinal tract should all be taken into account in estimating internal doses that result from use of water supplies contaminated with VOCs. INTERNAL EXPOSURE The concept of dose has been refined during the last 15-20 years.
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From page 70... ...
The peak blood concentration of carbon tetrachloride is about 10 times higher in the water-vehicle group than in the oil-vehicle group, but the relationships between blood concentrations of carbon tetrachloride and time in the two groups are essen
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From page 71... ...
In summary, VOCs that are extensively metabolized and quite volatile are most efficiently eliminated before they reach the arterial circulation. First-pass, or presystemic elimination, may have major implications for cancer and noncancer risks posed by ingestion of very low concentrations of VOCs in drinking water.
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From page 72... ...
Although bioavailability of carbon tetrachloride given in corn oil and in an aqueous Emulphor emulsion was the same, peak blood concentrations of carbon tetrachloride and acute hepatotoxicity were much lower in the corn oil group. Raymond and Plaa (1997)
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From page 73... ...
Arterial blood concentrations of carbon tetrachloride and the extent of acute hepatic damage were greater in the gavage groups. Carbon tetrachloride and other halocarbons are quickly absorbed from the gastrointestinal tract, and the rapid delivery of large quantities of carbon tetrachloride to the liver via the portal blood inhibited metabolism and killed hepatocytes.
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From page 74... ...
The relative extent of activation and inactivation of VOCs can vary substantially from one species to another and from one individual to another. It is well established that the metabolic activation of the VOCs of interest in Camp Lejeune water, in decreasing order of magnitude, is as follows: mice > rats > humans (Elfarra et al.
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From page 75... ...
. Metabolic activation of DCVC to chlorothioketene was shown to occur 11 times more rapidly in rats than in humans (Green et al.
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From page 76... ...
. Some trichloroacetic acid is converted to dichloroacetic acid.
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From page 77... ...
Rats subjected to an equivalent exposure excreted relatively large amounts of dichloroacetic acid, a rodent hepatic carcinogen. A small proportion of absorbed PCE undergoes conjugation with glutathione to form S-(1,2,2trichlorovinyl)
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From page 78... ...
. The extent of glutathione conjugation of PCE increases when the oxidative pathways begin to become saturated at high PCE exposure concentrations.
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From page 79... ...
TCE, PCE, and other solvents are well absorbed from the gastrointestinal tract of all age groups. The low plasma binding capacity of neonates should result in an increased rate of excretion of dichloroacetic acid and trichloroacetic acid, carcinogenic metabolites of TCE and PCE in mice, but it may be offset by neonates' larger extracellular water content, from which the metabolites have to be cleared.
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From page 80... ...
Although few data are available for TCE, PCE, and other VOCs, PBTK models predict a difference of no more than a factor of 2 in blood concentrations of VOCs after equivalent exposures of infants and adults. Newborns are predicted to have the highest blood concentrations and would be expected to be the most sensitive to any neurologic effects caused by high doses of the parent compounds.
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From page 81... ...
Another PBTK model's predictions of steady-state blood concentrations of PCE, vinyl chloride, and styrene were largely sex-independent (Sarangapani et al.
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From page 82... ...
PBTK model simulations of an 8-h inhalation exposure to TCE at 50 ppm and of consumption of 2 L of water containing TCE at 5 ppb revealed that the amount of VOC oxidized in the liver differed by only 2% in persons with the lowest and highest CYP2E1 content (Lipscomb et al.
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From page 83... ...
In conclusion, genetic differences in metabolic activation of TCE by the oxidative pathway do not appear likely to influence toxic or carcinogenic risks posed by the chemical at the concentrations measured in mixed water supplies at Camp Lejeune. Polymorphisms that dictate the presence or absence of genes that code for isozymes that initiate metabolic activation of TCE via the glutathione conjugation pathway are more likely to influence susceptibility to TCE-induced kidney cancer.
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From page 84... ...
used a PBTK model to predict that a 10-fold increase in CYP2E1 activity in humans inhaling TCE at 10 ppm would result in only a 2% increase in TCE metabolism by the liver. Thus, increased bioactivation capacity due to ethanol or other factors should not increase risks of toxicity or cancer in Camp Lejeune residents because of their low exposures to TCE, 1,1-DCE, methylene chloride, vinyl chloride, benzene, or other extensively metabolized VOCs.
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From page 85... ...
. That does not occur after low exposures to TCE and other well-metabolized VOCs (such as benzene, vinyl chloride, and methylene chloride)
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From page 86... ...
PBTK modeling has been used by several research groups to predict the metabolic and toxicologic consequences of exposure to VOC mixtures. Competitive metabolic inhibition was evident in a PBTK-model approach to studying TCE and 1,1-DCE (El-Masri et al.
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From page 87... ...
That would not occur at the lower concentrations that were found in the water supplies at Camp Lejeune. SUMMARY Residents of homes supplied with contaminated water can be exposed orally by drinking the water, as well as by inhalation and dermal exposure when using heated water for bathing, showering, and washing clothes and dishes.
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From page 88... ...
Low concentrations of CYP2E1 in neonates and infants will result in increased TCE concentrations but low concentrations of oxidative metabolites. Conversely, children have a relatively large liver and high liver blood flow, placing them at greater risk than adults from effects of oxidative metabolites.
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From page 89... ...
Knowledge of mechanisms of chemical interactions largely involves the effect of one VOC on the metabolic activation of a second. Concurrent exposures to sufficiently high doses typically involve competitive metabolic inhibition, which results in increased concentrations of parent compounds and lower production of metabolites.
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