Assessing the Human Health Risks of Trichloroethylene Key Scientific Issues (2006) / Chapter Skim
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5 Reproductive and Developmental Toxicity
5 Reproductive and Developmental Toxicity
Pages 182-212
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From page 182... ...
. A study of male mice exposed to trichloroethylene via inhalation found significantly increased percentages of abnormal sperm at the highest test 182
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(2002) used an inhibitory CYP2E1 monoclonal antibody to demonstrate that the enzyme CYP2E1 is involved in trichloroethylene metabolism to chloral in both the testes and epididymides.
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From page 184... ...
. The authors concluded that exposure to trichloroethylene leads to impairment of sperm's fertilizing ability, which may be attributed to the trichloroethylene metabolites chloral hydrate and trichloroethanol (Xu et al.
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From page 185... ...
(2001) reported that a mixture of drinking water pollutants, including trichloroethylene, caused alterations in mating desire and ability, sperm quality, and Leydig cell function in rabbits.
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. The authors also performed in vitro studies of mouse eggs cultured with cauda epididymal sperm and trichloroethylene or its metabolites -- dichloroacetic acid, trichloroacetic acid, and trichloroethanol -- to assess the effects on fertilization.
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From page 187... ...
neonates exhibited a dose-related increase across groups. The authors concluded that oral exposure to trichloroethylene at doses below those that cause maternal toxicity did not affect fertility or pregnancy outcome and that the accumulation of trichloroethylene and trichloroacetic acid in ovaries, adrenal glands, and uteri had no impact on mating success.
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From page 188... ...
(1979) compared the effects of timing of exposure to trichloroethylene on reproductive outcomes of female Long-Evans hooded rats exposed to trichloroethylene by inhalation at concentrations of 1,800 ± 200 ppm.
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(1989, 1992) studied the trichloroethylene metabolites trichloroacetic acid and dichloroacetic acid in pregnant Long-Evans rats and found that both metabolites reduced body weight and growth and produced cardiac defects.
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They found an increased incidence of cardiac malformations with trichloroacetic acid at a concentration of 2,730 ppm (10.53% versus 2.15% in the cumulative control group; P = 0.0001 for fetuses and P = 0.0004 for affected litters)
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From page 191... ...
They found no statistically significant increases in the incidence of fetal heart malformations by litter or fetus for trichloroethylene or the two metabolites. The incidences were 4.5%, 3.3%, and 4.7% for trichloroethylene, trichloroacetic acid, and dichloroacetic acid, respectively.
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. The trichloroethylene metabolites dichloroacetic acid, trichloroacetic acid, trichloroethanol, and oxalic acid have also tested positive in the FETAX assay, but each was significantly less toxic than trichloroethylene.
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, or one of four chlorinated compounds (trichloroacetic acid, dichloroacetic acid, chloral hydrate, and trichloroacetyl chloride)
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1991] ; and smooth muscle -actin and transforming growth factor 3 [Nakajima et al.
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(Embryos treated with 40 ppm trichloroethylene were not assessed.) The authors also tested trichloroacetic acid in their whole embryo explant systems, and it too altered the distribution of cells in the endocardial cushions (Hoffman et al.
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Direct extrapolation of the results of direct embryo culture studies is limited because maternal absorption, excretion, and metabolism do not occur in in vitro systems. In addition, no conceptuses were exposed simultaneously to multiple haloacetic acids, all of which are frequently low-level water disinfection products, or to other common coexposure chemicals, including compounds metabolically upstream and downstream of the haloacetic acids, such as trichloroethylene and chloral hydrate.
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evaluations of spermatogenesis and sexual function among men with occupational exposure to high concentrations of trichloroethylene or trichloroethylene-related compounds. The following discussion provides a qualitative overview of the epidemiologic evidence.
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Trichloroethylene exposure appears to be associated with significantly smaller male infants, whether measured as a continuous variable or as a dichotomous variable (ATSDR 1998; Sonnenfeld et al.
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A full study is planned to include all confirmed cases of birth defects and childhood cancers and an assessment of exposure to trichloroethylene and other drinking water contaminants by modeling the water system.
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. The relative risk of congenital anomalies considered as a single entity was 3.1 (95 % CI = 1.1, 10.4)
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. In a model that included other similar halogens, the OR for the association between oral clefts and exposure to trichloroethylene at greater than 5 ppb increased to 3.5, whereas that of other halogenated compounds fell with trichloroethylene exposure included.
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An increased frequency of congenital heart disease was suspected in Tucson, Arizona, in 1973. In 1981, drinking water contaminated with trichloroethylene (up to 270 ppb [approximately 0.009 mg/kg/day for a 60 kg adult]
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The proportion of mothers who were both older and had presumed trichloroethylene exposure was more than 6-fold greater among case infants (with congenital heart defects) than among control infants (3.3% versus 0.5%)
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In analyses that adjusted for multiple demographic factors, the relative risk of poor growth in the eastern study area was greater than in the controls. The ORs were 1.44 (95% CI = 1.13-1.83)
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The geometric mean of the overall mean 8-hour exposure was 29.6 ppm, and the mean urinary trichloroacetic acid concentration was 22.4 mg per g of creatinine. Workers were divided into "high"- and "low"-exposure groups based on whether their normalized concentrations of trichloroacetic acid in urine was greater or less than 25 mg per g of creatinine, respectively.
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From page 206... ...
Seminal fluid from all eight subjects contained trichloroethylene, chloral, and trichloroethanol, whereas dichloroacetic acid and trichloroacetic acid were present in only two and one sample, respectively. Neither trichloroethylene nor its metabolites was detected in the five control male seminal fluid samples.
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Spontaneous abortion was associated with increased paternal exposure to solvents in general (adjusted OR = 2.3, 95% CI = 1.1, 5.0)
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. Furthermore, among patients with cleft palate only, the risk increased with the concentration and frequency of trichloroethylene exposure.
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Although the evidence suggests that trichloroethylene can generate such effects, the lowest-observed-adverse-effect level for human risk assessment remains unclear. Some information suggests that certain human subpopulations might be at increased risk because age, genetic polymorphisms, or disease (see Chapter 9)
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1988) , suggest that trichloroethylene, or one or more of its metabolites (trichloroacetic acid and dichloroacetic acid)
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Recommendations: Additional studies evaluating a lowest-observed-adverse-effect level and mode of action for trichloroethylene-induced develop mental effects are needed to determine the most appropriate species for human modeling. More information is needed on metabolic activation in the avian model to evaluate interspecies differences, tissue-specific concentrations of trichloroethylene and its metabo lites, and human data with better ascertainment of congenital heart disease and improved quantitative assessment of trichloroethylene exposures.
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212 ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE or permanent is unclear. The mode of action is unclear and might or might not relate to hormonal alterations.
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