A physiologically based kinetic modeling of ethyl tert-butyl ether in humans-An illustrative application of quantitative structure-property relationship and Monte Carlo simulation.

Although physiologically based kinetic (PBK) modeling is informative for the risk assessment of industrial chemicals, chemical-specific input values for partition coefficients and metabolic parameters, including Vmax and Km are mostly unavailable; however, in silico methods, such as quantitative structure-property relationship (QSPR) could fill the absence. To assess the PBK model validity using necessary toxicokinetic (TK) parameters predicted by QSPR, the PBK model of ethyl tert-butyl ether (ETBE) as a model substance was constructed, in which the values of the partition coefficients, Vmax, and Km of ETBE were predicted using those of the related chemicals previously reported in the literature, and toxicokinetics of inhaled ETBE were stochastically estimated using the Monte Carlo simulation. The calculated ETBE concentrations in venous blood were comparable to the measured values in humans, implying that the reproducibility of ETBE toxicokinetics in humans was established in this PBK model. The Monte Carlo simulation was used to conduct uncertainty and sensitivity analyses of the dose metrics in terms of maximum blood concentration (Cmax) and area under the blood concentration-time curve (AUC) and the estimated Cmax and AUC were highly and moderately reliable, respectively. Conclusively, the PBK model validity combined with in silico methods of QSPR was demonstrated in an ETBE model substance. QSPR-PBK modeling coupled with the Monte Carlo simulation is effective for estimating chemical toxicokinetics for which input values are unavailable and for evaluating the estimation validity.

A GIS-based evaluation of the effect of decontamination on effective doses due to long-term external exposures in Fukushima.

Despite the enormous cost of radiation decontamination, there has been almost no quantitative discussion on how much it would reduce the long-term external radiation exposure in the Evacuation Zone and Planned Evacuation Zone (restricted zone) in Fukushima. The aim of this study is to assess the effectiveness of decontamination and return options and to identify important parameters for estimating the long-term cumulated effective dose (CED) during 15, 30 and 70 year period using data on land-use, population and decontamination in the restricted zone (about 1100 km(2)) in Fukushima. Decontamination of the land is assumed to have a certain efficacy in terms of the reduction of CED. The EeCC (external exposure conversion coefficient) is the parameter having the greatest effect on the percentage of area having CED during the 30 years above 100 m Sv after decontamination, ranging from 13% (EeCC=0.2) to 55% (EeCC=0.6). Therefore, we recommend a detailed investigation of the EeCC in Japan.

Reproductive and developmental toxicity of hydrofluorocarbons used as refrigerants.

The present paper summarizes data on the reproductive and developmental toxicity of hydrofluorocarbons (HFCs), including pentafluoroethane (HFC-125), 1,1,1,2-tetrafluoroethane (HFC-134a), 1,1,1-trifluoroethane (HFC-143a), 1,1-difluoroethane (HFC-152a), difluoromethane (HFC-32) and 1,1,1,3,3-pentafluoropropane (HFC-245fa), used as refrigerants, published in openly available scientific literature. No developmental toxicity of HFC-125 was found even at 50,000 ppm in rats or rabbits. Although HFC-134a exhibited no dominant lethal effect or reproductive toxicity in rats, it caused low body weight in pre- and postnatal offspring and slightly retarded skeletal ossification in fetuses at 50,000 ppm in rats. No maternal or developmental toxicity was noted after exposure to HFC-143a even at 40,000 ppm in rats or rabbits or HFC-152a even at 50,000 ppm in rats. HFC-32 is slightly maternally and developmentally toxic at 50,000 ppm in rats, but not in rabbits. HFC-245fa caused decreases in maternal body weight and food consumption at 10,000 and 50,000 ppm and fetal weight at 50 000ppm. No evidence of teratogenicity for these HFCs was noted in rats or rabbits. There is limited information about the reproductive toxicity of these HFCs. Animal studies remain necessary for risk assessments of chemicals because it is difficult to find alternative methods to determine the toxic effects of chemicals. It is required to reduce emissions of organic vapors containing HFCs to reduce the risk of exposure.

Reproductive and developmental toxicity of degradation products of refrigerants in experimental animals.

The present paper summarizes the results of animal studies on the reproductive and developmental toxicity of the degradation products of refrigerants, including trifluoroacetic acid (TFA), carbon dioxide (CO(2)), carbon monoxide (CO), carbonyl fluoride (CF), hydrogen fluoride (HF) and formic acid (FA). Excessive CO(2) in the atmosphere is testicular and reproductive toxic, embryolethal, developmentally neurotoxic and teratogenic in experimental animals. As for CO, maternal exposure causes prenatal and postnatal lethality and growth retardation, skeletal variations, cardiomegaly, blood biochemical, immunological and postnatal behavioral changes, and neurological impairment in offspring of several species. Very early studies of CO in rats and guinea pigs reported fetal malformations in exposed dams. The results of toxicological studies on sodium fluoride (NaF) were used to obtain insight into the toxicity of CF and HF, because CF is rapidly hydrolyzed in contact with water yielding CO(2) and HF, and NaF is similar in kinetics and dynamics to HF. Increased fetal skeletal variation, but not malformation, was noted after the maternal administration of NaF. Rat multiple-generation studies revealed that NaF caused retarded ossification and degenerative changes in the lung and kidney in offspring. There is a lack of information about the toxicity of TFA and FA.

Quantitative identification of unknown exposure pathways of phthalates based on measuring their metabolites in human urine.

Humans are exposed to ubiquitous phthalates via multiple pathways. Exposures to phthalates have been estimated in some previous risk assessments in Japan based on point-of-contact measurement or scenario evaluation approaches. While the Japanese national government has regulated the use of di(2-ethylhexyl)phthalate (DEHP) and excluded several other phthalates from its regulation based on some of them, it is unclear whether such past exposure assessment studies fully assessed total human exposure to phthalates. In the present study, we measured their urinary metabolites, which show direct evidence of human exposure to phthalates. We recruited voluntary participants (N = 36) who agreed to donate urine samples, and measured the urinary concentrations of phthalate metabolites using enzymatic deconjugation, solid-phase extraction, and high-performance liquid-chromatography isotope-dilution tandem mass spectrometry. We then derived the daily intakes of their respective phthalates based on steady state assumption and finally compared them with the corresponding estimated daily intakes of each phthalate via diet and air derived from previous exposure or risk assessments in Japan. These comparisons showed that exposures to dimethyl phthalate, diethyl phthalate, and di-n-butyl phthalate via diet and air accounted for less than half of their respective total exposures. On the other hand, it appears that dietary intake was more predictive for the total exposure to n-butyl-benzyl phthalate and DEHP. The probabilities that the log normal distribution of each phthalate daily intake estimated from the present study exceeds the corresponding tolerable daily intake were estimated to be less than 10(-4).

Screening-level risk assessment of Di(2-ethylhexyl)phthalate for aquatic organisms using monitoring data in Japan.

Screening-level ecological risk assessments of di(2-ethylhexyl)phthalate (DEHP) for aquatic organisms in Japan were conducted using estimated statistical values based on surface water and sediment monitoring data and effect threshold values based on a large aquatic toxicity database. An alternative method is proposed to handle monitoring data that contain nondetects including multiple detection limits and to determine the statistical values of DEHP concentrations in Japanese surface waters. The No-Observed-Effect-Concentration (NOEC(water)) of DEHP for aquatic life of 77 micro g/L was determined giving equal importance to both physical effects probably caused by undissolved DEHP and to the intrinsic toxicity potentially caused by DEHP. The NOEC(sediment) of 615,000 micro g/kg was determined by the Equilibrium Partitioning (EqP) theory, conservatively assuming a threshold effect level in the water column as the water solubility of 3 micro g/L. The potential risks of DEHP in Japanese water environments were characterized simply by comparing the margin of exposure (MOE) with a specified uncertainty multiplier (UM). The MOE is expressed as the ratio of NOEC(water) or NOEC(sediment) to the expected environmental concentrations such as the 95th percentiles of the estimated DEHP concentration distributions for surface water or sediment. The results of risk characterization show that all MOE values calculated using the statistical values of DEHP concentrations in Japanese surface waters and sediments are above 10, indicating minimal risk. Although the DEHP concentrations of some surface water samples showed MOE values of less than 10, considering environmental chemistry such as bioavailable fractions and the form of existence of DEHP in a water environment, we conclude that the current levels of DEHP are of little concern to aquatic life in the majority of Japanese surface waters and sediments.

Evaluation of the effect of governmental control of human exposure to two phthalates in Japan using a urinary biomarker approach.

In Japan, the use of certain phthalates has been regulated. We analyzed the effectiveness of these measures using an analytical biomarker approach. We measured two phthalate metabolites, mono-n-butyl phthalate (MBP) and mono-2-ethylhexyl phthalate (MEHP) in urine samples from 36 participants using enzymatic deconjugation, offline solid phase extraction, and HPLC-ESI-MS/MS. From the levels measured and individual values of creatinine excretion rate the daily intake was determined and compared to each corresponding tolerable daily intake (TDI). The levels of urinary MBP and MEHP were < 1.8-280 and 0.76-25 microg/l, respectively. The ranges of the estimated daily intake of di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) from 35 adult urine samples were 0.22-4.5 and 0.37-7.3 microg/kg/ day, respectively. These values were lower than the corresponding TDIs. After comparing these values to previous exposure assessment data on DEHP in Japan, it could be seen that the DEHP intake dropped over the period from 1998 to 2001. Children were not covered in the present study, so the results may only be applicable to adults, not to the Japanese population at large. Even so, the small number of people in one specific geographic area cannot be considered representative of the adult Japanese population. In addition to MEHP, the secondary metabolites of DEHP, which are more suitable biomarkers should be measured in the future.

Dioxin health risk to infants using simulated tissue concentrations.

Dioxin concentrations in infant and child were simulated using physiologically based pharmacokinetic (PBPK) models developed for these groups. The infant model was validated by comparing the simulated concentration with the measured concentration from the literature, and they showed good agreement. Simulations with our PBPK model showed temporal patterns in concentrations in various tissues. For risk assessment, estimated concentrations of 29 dioxins in the liver were summed up in a toxic equivalency (TEQ) basis to be compared with actual 2,3,7,8-TCDD concentrations in rat liver associated with toxicity. Maximum liver concentrations in breast-fed and formula-fed infants were 16.8pg TEQ/g and 3.5pg TEQ/g, respectively. The level in breast-fed infant liver was approximately 1/300 of the level associated with hepatocellular carcinoma and 1/5 of the level found in maternal rat liver associated with alterations in reproductive organs in the next generation. Based on our analysis, the present contamination level is not safe enough, but further dose-response data is required for a quantitative risk assessment.

Simulation of dioxin accumulation in human tissues and analysis of reproductive risk.

Polychlorinated dibenzo-p-dioxin, polychlorinated dibenzofuran and dioxin-like polychlorinated biphenyl concentrations in human liver, kidney, fat, blood, muscle, richly perfused tissue (brain, lung etc.) and skin were simulated to assess the health risk for Japanese fetuses. A 40-year time course of dioxin accumulation via food ingestion was simulated using a physiologically based pharmacokinetic (PBPK) model. In richly perfused tissue, the concentration estimated by the PBPK model showed better agreement with measured concentrations than that calculated by the one-compartment model. Fetal dioxin concentration was simulated based on the assumption that the fetal concentration was almost equal to the concentration in the mother's richly perfused tissue. To assess the reproductive risk, the estimated concentration in human fetus was compared with that in rat fetus in which reproductive function showed signs of alteration by 2,3,7,8-TCDD in previous reports [Toxicol. Appl. Pharmacol. 114 (1992) 118; 146 (1997) 11; Toxicol. Sci. 53 (2000) 411; 57 (2000) 275]. The present daily intake of 2,3,7,8-TCDD is approximately 1/50 of the amount that leads to possible reproductive toxicity in the next generation. However, when 29 kinds of dioxin congeners are considered, the present level is 1/5 of the hazardous levels. For species extrapolation of dioxin risk, further study on tissue concentration versus toxicity is required.

Estimation of dioxin risk to Japanese from the past to the future.

The transport processes of seventeen 2,3,7,8-chlorinated congeners of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) from their major sources to humans were modeled to estimate the time course, from the past to the future, of the human health risk to the Japanese population. The comparison between measured and estimated values showed that the present modeling approach represented the background levels of congeners in the environment, daily intake, and body burden reasonably well, except for in the case of 2,3,7,8-TCDF. Although PCDD/Fs in herbicides have contributed greatly to the daily intake and body burden to the Japanese population in the past, the main sources of the present intake and burden of PCDD/Fs is estimated to be incinerators. The margin of exposure (MOE) for the risk of morphological reproductive alteration in female offspring exposed prenatally was calculated based on the estimated maternal body burden. The results indicated that the MOE values were in the single digits, implying that these values may not be sufficiently large to guarantee the safety of female offspring of mothers born in the 1950s, whereas the MOE values for female offspring born in and after the latter half of the 1990s may be sufficiently large to guarantee safety.

Determination of tissue-blood partition coefficients for a physiological model for humans, and estimation of dioxin concentration in tissues.

The tissue-blood partition coefficients for a physiologically based pharmacokinetic (PBPK) model were determined, and the concentrations of 17 congeners of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in tissues in Japanese people were estimated using the model. According to the PBPK model established by Lawrence and Gobas [Chemosphere 35 (1997) 427-452], we assumed a steady-state fugacity model for Japanese people in general, and set the route of PCDD/Fs exposure only from food intake. The required partition coefficients for liver, kidney, adipose, muscle, skin, bile, gut and viscera (richly perfused tissue) were calculated using available autopsy data from eight Japanese men and women who were not accidentally exposed to PCDD/Fs. For validation of the partition coefficients, estimated PCDD/F concentrations in liver, kidney, fat, blood and muscle using the model were compared to other two sets of measured concentration data in Japanese tissues. Good agreement was obtained between estimated data and measured data, and most of the measured data were within the simulated concentration range in liver, kidney, blood and muscle. From these results, our model and calculated partition coefficients seem applicable for the estimation of congener-specific concentrations in human tissues.

Possible range of dioxin concentration in human tissues: simulation with a physiologically based model.

In risk evaluation of dioxins, monitoring chemical concentrations in human tissues is an important step, and these concentration data can be utilized along with animal toxicity data for extrapolation of human manifestation. However large differences in dioxin concentrations usually exist even among individuals who have never been accidentally exposed to high quantities of dioxin, and this may cause problems in risk analysis. Body size, age, and history of food consumption are factors responsible for these interindividual differences in addition to exposure levels. Using a physiologically based pharmacokinetic (PBPK) model, the influence of differences in body weight, gastrointestinal absorption, and half-life and intake of dioxin were examined on tissue chemical concentration. Dioxin concentrations over a 40-yr time course in human liver, kidneys, fat, blood, muscle and richly perfused tissue were simulated for polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and coplanar polychlorinated biphenyls (CoPCBs). Model parameters such as tissue-blood partition coefficients for CoPCBs were prepared, and sensitivity analysis was also performed on these parameters. The range of tissue concentrations was approximately 0.17 to 4.1 times the standard concentration, which was calculated using standard model parameters. The simulated ranges included more than 80% of the individual anatomical data for 2,3,7,8-tetrachlorodibenzo-p-dioxin, 1,2,3,7,-pentachlorodibenzo-p-dioxin, and 3,3',4,4',5-pentachlorobiphenyl in liver, fat, and blood. These results suggest that differences in body weight, gastrointestinal absorption, and food intake behavior may partially explain variation in tissue concentrations among individuals, and the possible interindividual uncertainty, which is approximately 24 for the general Japanese population.