Assessing the Human Health Risks of Trichloroethylene Key Scientific Issues (2006) / Chapter Skim
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10 Mixtures
10 Mixtures
Pages 277-296
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From page 277... ...
In the body, trichloroethylene is metabolized into trichloroacetic acid, chloral hydrate, 2-chloroacetaldehyde, trichloroethanol, trichloroethanol glucuronide, and perhaps dichloroacetic acid. Because trichloroethylene is readily absorbed by all routes of exposure and extensively metabolized to multiple chemical species, exposure to trichloroethylene can be considered an exposure to a toxic mixture.
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From page 278... ...
Male and female weanling ICR mice were treated with a mixture of chlorinated alkanes and alkenes consisting of chloroform, 1,1-dichloroethane, 1,1-dichloroethylene, 1,1,1-trichloroethane, trichloroethylene, and tetrachloroethylene in drinking water for 16 and 18 months, respectively; male mice developed hepatocelluar neoplasms and female mice developed mammary adenocarcinoma (Wang et al.
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From page 279... ...
. Even at 45 weeks after last exposure to drinking water pollutants, mating desire or ability, sperm quality, and Leydig cell function were subnormal.
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. A dietary copper imbalance resulted in higher trichloroethylene-induced lung damage as evidenced by a larger number of vacuolated Clara cells (Giovanetti et al.
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From page 281... ...
(2001) reported that brominated haloacetates such as bromodichloroacetate, bromochloroacetate, and dibromoacetate appear at higher concentrations in drinking water than the chlorinated haloacetates dichloroacetic acid and trichloroacetic acid.
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From page 282... ...
When administered alone in drinking water, dichloroacetic acid increased both tumor number and tumor size in a dose-related manner. With trichloroacetic acid treatment, tumor numbers plateaued by 24 weeks at a high dose.
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From page 283... ...
Chloroform, a chlorine disinfection by-product found in drinking water, as well as dichloroacetic acid and trichloroacetic acid, is also a mouse liver carcinogen and was the focus of another study by Pereira et al.
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From page 284... ...
No foci of altered hepatocytes were found in N-methyl-N-nitrosourea-initiated control mice of either sex. A larger number of foci of altered hepatocytes were seen in female than in male mice after N-methyl-N-nitrosourea and dichloroacetic acid treatment, although the number of tumors per mouse was about the same.
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From page 285... ...
or multiplicity of N-methyl-N-nitrosourea-initiated kidney tumors, but coexposure with chloroform increased the incidence of kidney tumors to 100% in male mice. In female mice, kidney tumor incidence and multiplicity after trichloroacetic acid or dichloroacetic acid treatment with or without chloroform was low after initiation with N-methyl-N-nitrosourea.
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From page 286... ...
Lower tolerance to the inebriating effects of alcohol among workers exposed to trichloroethylene has been well documented. A condition known as "degreasers flush" is seen in subjects exposed to trichloroethylene, where dilation of blood vessels in the skin surface occurs with consumption of small amounts of alcohol (Stewart et al.
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From page 287... ...
as cofactor. Alternatively, chloral hydrate can be converted to trichloroethanol by alcohol dehydrogenase.
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From page 288... ...
Nevertheless, the study shows that a larger supply of reducing equivalents by alcohol metabolism favors the formation of trichloroethanol over trichloroacetic acid, which was highly predictable based on the form of NADH needed to catalyze the different chloral hydrate biotransformation reactions. The effect of ethanol on trichloroethylene metabolism has also been investigated in isolated perfused rat livers (Watanabe et al.
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From page 289... ...
Although ethanol oxidation by liver alcohol dehydrogenase is the ratelimiting step in the total oxidation of this alcohol, ethanol oxidation also occurs via CYP450. This alternative metabolic pathway for ethanol is more pronounced with chronic alcohol consumption due to the well-documented CYP2E1 induction that occurs with chronic exposure.
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From page 290... ...
by changing the ratio of pyridine dinucleotide cofactors needed to convert chloral hydrate
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From page 291... ...
. Chloroform, when coadministered with dichloroacetic acid and trichloroacetic acid (metabolites of trichloroethylene)
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From page 292... ...
. Early exposure of male rabbits to a mixture of arsenic, chromium, lead, benzene, chloroform, phenol, and trichloroethylene in drinking water caused acrosomal dysgenesis, nuclear malformations, lower testosterone secretion, subnormal mating desire and ability, lower sperm quality, and decreased Leydig cell function (Veeramachaneni et al.
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. Pretreatment with drinking water solutions containing trichloroethylene or chloroform enhances the hepatotoxicity of carbon tetrachloride in Fischer 344 rats (Steup et al.
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24 ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE amounts almost twice as high as the expected rates of increase in the parent compound blood concentrations. The authors suggested that using parent blood concentrations (a less sensitive biomarker)
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MIXTURES 2 study were consistent with metabolic inhibition. The 10-chemical mixture was the most complex coexposure used in this study.
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From page 296... ...
26 ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE Studies designed to learn more about mechanisms and modes of action in the presence of the most commonly occurring toxicants are likely to yield the most meaningful results. · Testing to evaluate the impact of lifestyle factors, such as alcohol consumption, smoking, chronic drug intake, and diet (e.g., nutri tion, caloric restriction)
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