Assessing the Human Health Risks of Trichloroethylene Key Scientific Issues (2006) / Chapter Skim
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9 Special Population and Susceptibility
9 Special Population and Susceptibility
Pages 253-276
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From page 253... ...
. Children have been identified as a special population to consider in risk assessment because their health risks can differ from those of adults as a result of their immature physiology, metabolism, and different levels of exposure (EPA 1996, 2005b)
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Chapter 2 provides guidelines for conducting a more rigorous review of the epidemiologic data. The effects of parental occupational exposure on the risk of childhood cancer have been studied epidemiologically for more than 25 years.
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. Early studies on paternal occupational exposures suggest that exposure to trichloroethylene conveys a risk of leukemia and brain cancer developing in the offspring.
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Approaches to Developmental Risk Assessment Approaches defined under the new EPA guidelines for adult cancer risk assessment includes flexibility and the use of biologically based response models when appropriate (EPA 2005a)
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Using developmental physiologically based pharmacokinetic (PBPK) modeling with parameter estimates appropriate for children: Such models can improve the development of relative-risk information for a specific xenobiotic exposure (Ginsberg et al.
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. Trichloroethylene is metabolized to chloral, which spontaneously hydrates to form chloral hydrate (Byington and Leibman 1965)
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From page 259... ...
. The metabolism of chloral hydrate depends on two forward pathways (oxidation to trichloroacetic acid and reduction to trichloroethanol)
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This includes information about the developmental profiles of CYP2E1, alcohol dehydrogenase, and aldehyde dehydrogenase, as well as studies of the disposition of chloral hydrate in children. The developmental profile of CYP2E1, the enzyme responsible for the rate-limiting step, has been well characterized across fetal and pediatric age groups (Johnsrud et al.
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From page 261... ...
In a rodent model, trichloroacetic acid was found to cycle from the fetus into the amniotic fluid and back into the fetus (Ghantous et al.
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Differences in human alcohol dehydrogenase might be of equal or greater relevance to human trichloroethylene risk assessment compared with CYP2E1. Although CYP2E1 is the rate-limiting enzyme, the halogenated acetic acids trichloroacetic acid and dichloroacetic acid have been suggested as the proximate putative teratogenic species (Johnson et al.
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From page 263... ...
. Which aldehyde dehydrogenase isoforms are capable of and most efficient at metabolizing chloral hydrate to trichloroacetic acid is unknown but needs to be determined.
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In contrast, pulmonary expression of GSTM, GSTA1, and GSTA2 are relatively low, but consistent, across gestation. Chloral Hydrate and Dichloroacetic Acid Studies in Children The trichloroethylene metabolite chloral hydrate has been used as a sedative for more than 150 years and is prescribed frequently for children, usually as a single dose for procedural sedation.
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dichloroacetic acid, or with two chloral hydrate doses before and after a dose of [13C] dichloroacetic acid.
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. Chloral hydrate, trichloroethanol, and trichloroacetic acid were the same or higher in 50%, 63%, and 57% of cord blood samples, respectively, compared with paired maternal blood samples.
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SPECIAL POPULATIONS AND SUSCEPTIBILITY 26 genetiC susCePtiBility Currently, 114 human CYP2E1 single nucleotide polymorphisms have been reported to the National Center for Biotechnology Information database dbSNP. Of these, 65 have been validated.
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. Monte Carlo analyses of the variability factors of other somewhat similar compounds, such as ethanol and toluene, suggest that the default pharmacokinetic uncertainty factor is not sufficient to account for the ALDH2*
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Predicting the human cancer or noncancer risks in humans depends on the specific gene and polymorphism expressed. Data for trichloroethylene are incomplete; which GST isoforms are most efficient in trichloroethylene disposition is unknown.
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. Human vaRiaBility and tHe use of unCeRtainty faCtoRs Uncertainty factors are applied to risk estimates to account for variability in human populations as well as other factors.
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, the use of this lesser factor is supported by qualitative information presented in EPA's discussion of the uncertainty factors.
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, which details the uncertainty in human risks of liver tumors based on an analysis of mouse liver tumors using trichloroacetic acid and dichloroacetic acid as an internal dose measure. The uncertainty for human potency in producing liver tumors is estimated by assuming the toxic equivalency of 3From EPA (2001b, p.
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EPA has attempted to account for human variability, particularly for vulnerable populations, with an array of uncertainty factors. EPA is encouraged to increase the precision of risk estimates used for fetuses and children with PBPK modeling approaches similar to that used for adults.
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· Improved information on dermal absorption and alterations in risk from developmental differences in skin thickness, as well as surface area and body weight determinations, is needed. · If interspecies differences are determined to be predominantly related to compound disposition, PBPK models that incorporate critical comparative biology and physiology can be used to ex trapolate developmental studies in animals to humans.
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From page 276... ...
26 ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE ticularly with low-dose chronic exposure. It is possible that existing data sets could be mined for pertinent information, particularly for common disorders or factors, such as diabetes, obesity, and alcohol consumption.
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