Metabolism and lipoperoxidative activity of trichloroacetate and dichloroacetate in rats and mice

Larson, Jeffrey; Bull, Richard J.

doi:10.1016/0041-008x(92)90332-m

Cited by 139 publications

(115 citation statements)

References 27 publications

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“…This leads to high residual errors (a = 0.79). Figure 3 presents the fit to the mouse data of Fisher et al (13) (14) may be too high (the model underpredicts them by a factor of 2 or 2.5), but this may be simply due to noise in the data.…”

Section: Resultsmentioning

confidence: 99%

“…Fisher et al (13) exposed groups of 14 female B6C3F, mice each (bw 26.5 g) by inhalation to TCE in a closed chamber of 9.1 L, at concentrations of 300, 700, 1,100, 3,700, and 7,000 ppm (groups 7-11) and groups of 15 male mice (bw 31 g) each to 1,020, 1,800, 3,800, 5,600, and 10,000 ppm (groups [12][13][14][15][16]. The concentration of TCE in the air chamber was measured.…”

Section: Methods Datamentioning

confidence: 99%

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Statistical analysis of Clewell et al. PBPK model of trichloroethylene kinetics.

Bois

2000

Environ Health Perspect

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A physiologically based pharmacokinetic model for trichloroethylene (TCE) in rodents and humans was calibrated with published toxicokinetic data sets. A Bayesian statistical framework was used to combine previous information about the model parameters with the data likelihood, to yield posterior parameter distributions. The use of the hierarchical statistical model yielded estimates of both variability between experimental groups and uncertainty in TCE toxicokinetics. After adjustment of the model by Markov chain Monte Carlo sampling, estimates of variability for the animal or human metabolic parameters ranged from a factor of 1.5-2 (geometric standard deviation [GSDI). Uncertainty was of the same order as variability for animals and higher than variability for humans. The model was used to make posterior predictions for several measures of cancer risk. These predictions were affected by both uncertainties and variability and exhibited GSDs ranging from 2 to 6 in mice and rats and from 2 to 10 for humans. The recent development of a comprehensive physiologically based pharmacokinetic (PBPK) model of trichloroethylene (TCE) disposition and metabolism in mice, rats, and humans (1) offers us the opportunity to examine issues of variability and uncertainty for that solvent. In particular, uncertainties in prediction of various cancer dose metrics deserve to be computed, since they could be directly used as input for improved risk assessments.PBPK modeling provides a strong mechanistic basis for prediction of disposition and metabolism of toxicants. Yet much uneasiness remains with the use of these models in toxicology (2). Similarly, as discussed in a recent review and an accompanying commentary, PBPK modeling has not seen the development it promised for therapeutic compounds (3,4). The reason for this essentially lies in the lack of statistical methods for calibrating these models. Because of individual variability and uncertainty, many parameters are difficult to measure accurately even for inbred animal strains. Using input parameters or presenting results in the form of a single value can therefore be very misleading (5). In the absence of rigorous statistical treatment, inference presented by PBPK modeling is largely empirical, hypotheses are left unvalidated, and predictions lack realistic measures of uncertainty. This state of affairs is unfortunate, when considering the consequences (for public health and national welfare) of the decisions made using these models.Obviously, correct statistical treatment of PBPK models is difficult, since these are large nonlinear models with relatively small data sets and a high degree of uncertainty and biological variability (6). It is also essential to respect the fundamental specificity of PBPK models, i.e., their high prior information content, which they provide through the opportunity to use physiological information on parameter values. Yet, although several parameters have physiological meaning and a narrow range of possible values, others-often specific of the com...

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Section: Resultsmentioning

confidence: 99%

Section: Methods Datamentioning

confidence: 99%

Statistical analysis of Clewell et al. PBPK model of trichloroethylene kinetics.

Bois

2000

Environ Health Perspect

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“…Other compounds such as trichloroethanol, trichloroacetic acid and dichloroacetic acid have all been shown to induce lipid peroxidation, a biomarker of oxidative stress, presumably via a free radical mechanism (Larson & Bull 1992;Ni et al 1996).…”

Section: (B) Oxidative Stressmentioning

confidence: 99%

The epidemiology and possible mechanisms of disinfection by-products in drinking water

Nieuwenhuijsen

Grellier

Smith

et al. 2009

Phil. Trans. R. Soc. A.

127

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This paper summarizes the epidemiological evidence for adverse health effects associated with disinfection by-products (DBPs) in drinking water and describes the potential mechanism of action.There appears to be good epidemiological evidence for a relationship between exposure to DBPs, as measured by trihalomethanes (THMs), in drinking water and bladder cancer, but the evidence for other cancers including colorectal cancer is inconclusive and inconsistent. There appears to be some evidence for an association between exposure to DBPs, specifically THMs, and little for gestational age/intrauterine growth retardation and, to a lesser extent, pre-term delivery, but evidence for relationships with other outcomes such as low birth weight, stillbirth, congenital anomalies and semen quality is inconclusive and inconsistent. Major limitations in exposure assessment, small sample sizes and potential biases may account for the inconclusive and inconsistent results in epidemiological studies. Moreover, most studies have focused on total THMs as the exposure metric, whereas other DBPs appear to be more toxic than the THMs, albeit generally occurring at lower levels in the water.The mechanisms through which DBPs may cause adverse health effects including cancer and adverse reproductive effects have not been well investigated. Several mechanisms have been suggested, including genotoxicity, oxidative stress, disruption of folate metabolism, disruption of the synthesis and/or secretion of placental syncytiotrophoblast-derived chorionic gonadotropin and lowering of testosterone levels, but further work is required in this area.

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“…In human populations, exposure to DBPs in the presence of some polymorphisms of CYP2E1 has been related to an increased risk of bladder cancer [17]. The mechanism of TCAA is different, either excreted unchanged due to polar binding to plasma proteins or following a free radical-generating reductive dechlorination pathway into dichloroacetic acid which is a more potent lipoperoxidative compound [18]. In addition, other compounds may act as precursors of TCAA (chloral hydrate or trichloroethanol) [19].…”

Section: Experimental Evidence and Mechanisms Of Actionmentioning

confidence: 99%

Overview of Disinfection By-products and Associated Health Effects

Villanueva

Cordier²,

Font-Ribera

et al. 2015

Curr Envir Health Rpt

217

124

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The presence of chemical compounds formed as disinfection by-products (DBPs) is widespread in developed countries, and virtually whole populations are exposed to these chemicals through ingestion, inhalation, or dermal absorption from drinking water and swimming pools. Epidemiological evidence has shown a consistent association between long-term exposure to trihalomethanes and the risk of bladder cancer, although the causal nature of the association is not conclusive. Evidence concerning other cancer sites is insufficient or mixed. Numerous studies have evaluated reproductive implications, including sperm quality, time to pregnancy, menstrual cycle, and pregnancy outcomes such as fetal loss, fetal growth, preterm delivery, and congenital malformation. The body of evidence suggests only minor effects from high exposure during pregnancy on fetal growth indices such as small for gestational age (SGA) at birth. Populations highly exposed to swimming pools such as pool workers and professional swimmers show a higher prevalence of respiratory symptoms and asthma, respectively, although the direction of the association, and thus causality, is not clear among professional swimmers. The risk of asthma, wheezing, eczema, and other respiratory outcomes among children attending swimming pools has been the object of extensive research. Early studies suggested a positive association, while subsequent larger studies found no correlations or showed a protective association. Future research should develop methods to evaluate the effects of the DBP mixture and the interaction with personal characteristics (e.g., genetics, lifestyle), clarify the association between swimming pools and respiratory health, evaluate the occurrence of DBPs in lowand middle-income countries, and evaluate outcomes suggested by animal studies that have not been considered in epidemiological investigations.

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Metabolism and lipoperoxidative activity of trichloroacetate and dichloroacetate in rats and mice

Cited by 139 publications

References 27 publications

Statistical analysis of Clewell et al. PBPK model of trichloroethylene kinetics.

Statistical analysis of Clewell et al. PBPK model of trichloroethylene kinetics.

The epidemiology and possible mechanisms of disinfection by-products in drinking water

Overview of Disinfection By-products and Associated Health Effects

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