The THMs are absorbed, metabolized and eliminated rapidly by mammals after oral or inhalation exposure. Following absorption, the highest tissue concentrations are attained in the fat, liver and kidneys. Half-lives generally range from 0.5 to 3 h, and the primary route of elimination is via metabolism to carbon dioxide. Metabolic activation to reactive intermediates is required for THM toxicity, and the three brominated species are all metabolized more rapidly and to a greater extent than chloroform. The predominant route of metabolism for all the THMs is oxidation via cytochrome P450 (CYP) 2E1, leading to the formation of dihalocarbonyls (i.e., phosgene and brominated congeners), which can be hydrolysed to carbon dioxide or bind to tissue macromolecules. Secondary metabolic pathways are reductive dehalogenation via CYP2B1/2/2E1 (leading to free radical generation) and glutathione (GSH) conjugation via glutathione- S-transferase (GST) T1-1, which generates mutagenic intermediates. The brominated THMs are much more likely than chloroform to proceed through the secondary pathways, and GST-mediated conjugation of chloroform to GSH can occur only at extremely high chloroform concentrations or doses
The kinetics and metabolism of the dihaloacetic and trihaloacetic acids differ significantly. To the extent they are metabolized, the principal reactions of the trihaloacetic acids occur in the microsomal fraction, whereas more than 90% of the dihaloacetic acid metabolism, principally by glutathione transferases, is observed in the cytosol. TCA has a biological half-life in humans of 50 h. The half-lives of the other trihaloacetic acids decrease significantly with bromine substitution, and measurable amounts of the dihaloacetic acids can be detected as products with brominated trihaloacetic acids. The half-lives of the dihaloacetic acids are very short at low doses but can be drastically increased as dose rates are increased.
Haloaldehydes and haloketones
Limited kinetic data are available for chloral hydrate. The two major metabolites of chloral hydrate are trichloroethanol and TCA. Trichloroethanol undergoes rapid glucuronidation, enterohepatic circulation, hydrolysis and oxidation to TCA. Dechlorination of trichloroethanol or chloral hydrate would lead to the formation of DCA. DCA may then be further transformed to monochloroacetate (MCA), glyoxalate, glycolate and oxalate, probably through a reactive intermediate. No information was found on the other haloaldehydes and haloketones.
The metabolism and kinetics of HANs have not been studied. Qualitative data indicate that the products of metabolism include cyanide, formaldehyde, formyl cyanide and formyl halides.
Halogenated hydroxyfuranone derivatives
3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is the member of the hydroxyfuranone class that has been most extensively studied. From animal studies, it appears that the 14C label of MX is rapidly absorbed from the gastrointestinal tract and reaches systemic circulation. MX itself has not been measured in blood. The MX label is largely excreted in urine and faeces, urine being the major route of excretion. Very little of the initial radiolabel is retained in the body after 5 days.