A Physiologically Based Pharmacokinetic Assessment of Tetrachloroethylene in Groundwater for a Bathing and Showering Determination

A two-step methodology is described to make a health-based determination for the bathing and showering use of the water from a private well contaminated with volatile organic chemicals. The chemical perchloroethylene (PERC) is utilized to illustrate the approach. First, a chemical-specific exposure model is used to predict the concentration of PERC in the shower air, shower water, and in the air above the bathtub. Second, a physiologically based pharmacokinetic (PBPK) model is used to predict the concentration of PERC delivered to the target tissue, the brain, since the focus is on neurological endpoints. The simulation exercise includes concurrent dermal and inhalation routes of exposure. A reference target tissue level (RTTL) in the brain is estimated using the PBPK model. A hazard index based on this benchmark guideline is used to make a regulatory determination for bathing and showering use of the contaminated water.     

Methyl tert Butyl Ether Systemic Toxicity

In male F344 rats exposed in a chronic inhalation study to methyl tertiary butyl ether (MTBE) a treatment related increase in severity of chronic nephropathy and mortality and an increase in hyaline droplets in the kidney were noted. Liver weights were increased in both rats and mice but no histological lesions other than hypertrophy are seen. Transient CNS effects but no indications of permanent nervous system effects were noted. MTBE is not a reproductive or developmental hazard. MTBE is rapidly absorbed. MTBE with some metabolite, tertiary butyl alcohol (TBA) and a little CO₂, are excreted in the air. The urinary excretion products in animals are TBA metabolites, while in humans the urinary excretion products are MTBE and TBA. A comparison of the systemic responses of the possible metabolites TBA and formaldehyde indicate that they are not responsible for toxicity associated with MTBE, except that TBA may be partially responsible for the kidney effects reported. Animals and humans are similar in the uptake and excretion though with some differences in metabolism of MTBE. This supports the use of the animal data as a surrogate for humans.     

Carcinogenicity Studies on MTBE: Critical Review and Interpretation

Chronic inhalation of toxic concentrations of MTBE caused renal tubular cell neoplasms in male Fischer 344 rats and hepatocellular adenomas in female CD-1 mice. In Sprague-Dawley rats the oral administration of MTBE was associated with increased incidences of Leydig cell tumors and of lymphomas and leukemias (combined) in males and females, respectively. Neither lymphomas nor leukemias were individually increased in treated females. Leydig cell tumors are common in rats and do not predict human responses to drugs and chemicals. Neither MTBE nor its metabolite, t -butyl alcohol, possess mutagenic potential and a second metabolite, formaldehyde, is mutagenic in vitro but in vivo results are equivocal. MTBE-induced neoplasms are most likely produced through a nongenetic mechanism which requires chronic exposure to toxic doses. Because of the intense odor (and taste) of MTBE, humans will not tolerate either air or water concentrations sufficient to produce the cytotoxic precursors required to promote cellular proliferation.     

A Comparative Cancer Risk Evaluation of MTBE and Other Compounds (Including Naturally Occurring Compounds) in Drinking Water in New Hampshire

Methyl tert-butyl ether (MTBE) was added to gasoline in New Hampshire (NH) between 1995 and 2006 to comply with the oxygenate requirements of the 1990 Amendments to the Clean Air Act. Leaking tanks and spills released MTBE into groundwater, and as a result, MTBE has been detected in drinking water in NH. We conducted a comparative cancer risk assessment and a margin-of-safety (MOS) analysis for several constituents, including MTBE, detected in NH drinking water. Using standard risk assessment methods, we calculated cancer risks from exposure to 12 detected volatile organic compounds (VOCs), including MTBE, and to four naturally occurring compounds (i.e., arsenic, radium-226, radium-228, and radon-222) detected in NH public water supplies. We evaluated exposures to a hypothetical resident ingesting the water, dermally contacting the water while showering, and inhaling compounds volatilizing from water in the home. We then compared risk estimates for MTBE to those of the other 15 compounds. From our analysis, we concluded that the high-end cancer risk from exposure to MTBE in drinking water is lower than the risks from all the other VOCs evaluated and several thousand times lower than the risks from exposure to naturally occurring constituents, including arsenic, radium, and radon. We also conducted an MOS analysis in which we compared toxicological points of departure to the NH maximum contaminant level (MCL) of 13 µg/L. All of the MOSs were greater than or equal to 160,000, indicating a large margin of safety and demonstrating the health-protectiveness of the NH MCL for MTBE.     

Risk Characterization of Methyl tertiary Butyl Ether (MTBE) in Tap Water

Methyl tertiary butyl ether (MTBE) can enter surface water and groundwater through wet atmospheric deposition or as a result of fuel leaks and spills. About 30% of the U.S. population lives in areas where MTBE is in regular use. Ninety-five percent of this population is unlikely to be exposed to MTBE in tap water at concentrations exceeding 2 ppb, and most will be exposed to concentrations that are much lower and may be zero. About 5% of this population may be exposed to higher levels of MTBE in tap water, resulting from fuel tank leaks and spills into surface or groundwater used for potable water supplies. This paper describes the concentration ranges found and anticipated in surface and groundwater, and estimates the distribution of doses experienced by humans using water containing MTBE to drink, prepare food, and shower/bathe. The toxic properties (including potency) of MTBE when ingested, inhaled, and in contact with the skin are summarized. Using a range of human toxic potency values derived from animal studies, margins of exposure (MOE) associated with alternative chronic exposure scenarios are estimated to range from 1700 to 140,000. Maximum concentrations of MTBE in tap water anticipated not to cause adverse health effects are determined to range from 700 to 14,000 ppb. The results of this analysis demonstrate that no health risks are likely to be associated with chronic and subchronic human exposures to MTBE in tap water. Although some individuals may be exposed to very high concentrations of MTBE in tap water immediately following a localized spill, these exposures are likely to be brief in duration due to large-scale dilution and rapid volatilization of MTBE, the institution of emergency response and remediation measures to minimize human exposures, and the low taste and odor thresholds of MTBE which ensure that its presence in tap water is readily detected at concentrations well below the threshold for human injury.     

The Risk of MTBE Relative to Other VOCs in Public Drinking Water in California

Ongoing publicity about methyl tertiary butyl ether (MTBE) suggests that this chemical is of greater concern than other contaminants commonly found in drinking water. The purpose of this article is to evaluate the available MTBE data in context with other volatile organic compounds (VOCs) that are detected in public drinking water sources in California. We find that of the 28 VOCs with a primary maximum contaminant level (MCL) in California, 21 were found in 50 or more drinking water sources from 1985 to 2002. Over the last 10 years, the most frequently detected VOCs were chloroform, tetrachloroethylene (PCE), and trichloroethylene (TCE), which were found in about 9-15% of all sampled drinking water sources. These same chemicals were found to have the highest mean detected concentrations over the last 5 years, ranging from 13 to 15 microg/L. Many VOCs were also found to routinely exceed state and federal drinking water standards, including benzene and carbon tetrachloride. By comparison, MTBE was found in approximately 1% of sampled drinking water sources for most years, and of those drinking water sources found to contain MTBE from 1998 to 2002, over 90% had detected concentrations below California's primary MCL of 13 microg/L. Relative to the other VOCs evaluated, MTBE has the lowest estimated California cancer potency value, and was found to pose one of the least cancer risks from household exposures to contaminated drinking water. These findings suggest that MTBE poses an insignificant threat to public drinking water supplies and public health in California, particularly when compared to other common drinking water contaminants.     

Development of a Screening Approach to Interpret Human Biomonitoring Data on Volatile Organic Compounds: Reverse Dosimetry on Biomonitoring Data for Trichloroethylene

A screening approach is developed for volatile organic compounds (VOCs) to estimate exposures that correspond to levels measured in fluids and/or tissues in human biomonitoring studies. The approach makes use of a generic physiologically-based pharmacokinetic (PBPK) model coupled with exposure pattern characterization, Monte Carlo analysis, and quantitative structure property relationships (QSPRs). QSPRs are used for VOCs with minimal data to develop chemical-specific parameters needed for the PBPK model. The PBPK model is capable of simulating VOC kinetics following multiple routes of exposure, such as oral exposure via water ingestion and inhalation exposure during shower events. Using published human biomonitoring data of trichloroethylene (TCE), the generic model is evaluated to determine how well it estimates TCE concentrations in blood based on the known drinking water concentrations. In addition, Monte Carlo analysis is conducted to characterize the impact of the following factors: (1) uncertainties in the QSPR-estimated chemical-specific parameters; (2) variability in physiological parameters; and (3) variability in exposure patterns. The results indicate that uncertainty in chemical-specific parameters makes only a minor contribution to the overall variability and uncertainty in the predicted TCE concentrations in blood. The model is used in a reverse dosimetry approach to derive estimates of TCE concentrations in drinking water based on given measurements of TCE in blood, for comparison to the U.S. EPA's Maximum Contaminant Level in drinking water. This example demonstrates how a reverse dosimetry approach can be used to facilitate interpretation of human biomonitoring data in a health risk context by deriving external exposures that are consistent with a biomonitoring data set, thereby permitting comparison with health-based exposure guidelines.     

Exposure to Chlorination By-Products from Hot Water Uses

Exposures to chlorination by-products (CBP) within public water supplies are multiroute in water. Cold water is primarily used for ingestion while a mixture of cold water and hot water is used for showering, bathing others, dish washing, etc. These latter two activities result in inhalation and dermal exposure. Heating water was observed to change the concentration of various CBP. An increase in the trihalomethanes (THM) concentrations and a decrease in the haloacetonitriles and halopropanones concentration, though an initial rise in the concentration of dichloropropanone, were observed. The extent of the increase in the THM is dependent on the chlorine residual present. Therefore, estimates of total exposure to CBP from public water supplies need to consider any changes in their concentration with different water uses. The overall THM exposures calculated using the THM concentration in heated water were 50% higher than those calculated using the THM concentration present in cold water. The estimated lifetime cancer risk associated with exposure to THM in water during the shower is therefore underestimated by 50% if the concentration of THM in cold water is used in the risk assessment.     

Duration Adjustment of Acute Exposure Guideline Level Values for Trichloroethylene Using a Physiologically-Based Pharmacokinetic Model

Acute Exposure Guideline Level (AEGL) recommendations are developed for 10-minute, 30-minute, 1-hour, 4-hours, and 8-hours exposure durations and are designated for three levels of severity: AEGL-1 represents concentrations above which acute exposures may cause noticeable discomfort including irritation; AEGL-2 represents concentrations above which acute exposure may cause irreversible health effects or impaired ability to escape; and AEGL-3 represents concentrations above which exposure may cause life-threatening health effects or death. The default procedure for setting AEGL values across durations when applicable data are unavailable involves estimation based on Haber's rule, which has an underlying assumption that cumulative exposure is the determinant of toxicity. For acute exposure to trichloroethylene (TCE), however, experimental data indicate that momentary tissue concentration, and not the cumulative amount of exposure, is important. We employed an alternative approach to duration adjustments in which a physiologically-based pharmacokinetic (PBPK) model was used to predict the arterial blood concentrations [TCE(a)] associated with adverse outcomes appropriate for AEGL-1, -2, or -3-level effects. The PBPK model was then used to estimate the atmospheric concentration that produces equivalent [TCE(a)] at each of the AEGL-specific exposure durations. This approach yielded [TCE(a)] values of 4.89 mg/l for AEGL-1, 18.7 mg/l for AEGL-2, and 310 mg/l for AEGL-3. Duration adjustments based on equivalent target tissue doses should provide similar degrees of toxicity protection at different exposure durations.     

Short-Term Dermal Absorption and Penetration of Chemicals from Aqueous Solutions: Theory and Experiment

Dermal penetration of organic chemical-contaminated water from showering and bathing scenarios is a concern of regulatory agencies that have been tasked with determining safe exposure levels. During household showering and bathing, nearly the entire surface area of the body is exposed for short periods of time (5-15 minutes). The primary means of predicting body burden during brief exposures is to estimate total chemical penetrated from the steady-state penetration rate using a skin permeability coefficient. A variety of approaches has been recommended to estimate "body burden." The purpose of this investigation was to collect experimental data from short-term exposures to an organic chemical (dibromomethane [DBM]) in aqueous solution so that methods for estimating body burden could be compared. Rat skins were exposed in vitro to saturated aqueous solutions of DBM for 20 minutes and the amount of chemical in the receptor solution and the skin was analyzed. The total DBM mass in the receptor solution and the skin was taken to represent an in vivo body burden. These results were compared with the estimates of penetration from steady-state calculations, square root of time calculations, and a biologically based mathematical model. Results indicated that the amount of chemical in the skin and its fate during short exposures is important. The square root of time approach predicted total amount of chemical absorbed and penetrated better than did the steady-state approach. The biologically based mathematical model accurately predicted total body burden and could be used to distinguish between the amount of chemical in the skin and the amount of chemical that penetrated through the skin, which would be useful for understanding local toxicity.     

Linking Indoor Air and Pharmacokinetic Models to Assess Tetrachloroethylene Risk

Physiologically based pharmacokinetic (PBPK) models describing the uptake, metabolism, and excretion of xenobiotic compounds are now proposed for use in regulatory health-risk assessments. In this study we investigate the extent of PCE metabolism arising from domestic respiratory exposure to tetrachloroethylene (PCE) from ground water, as predicted using a PBPK model. Indoor exposure patterns we use as input to the PBPK model are realistic ones generated from a three-compartment model describing volatilization of PCE from domestic water into household air. Values we use for the metabolic parameters of the PBPK model are estimated from data on urinary metabolites in workers exposed to PCE. It is shown that for respiratory PCE exposure due to typical levels of PCE in ground water, use of time-weighted average air concentrations with a steady-state PBPK model yields estimates of total metabolized PCE similar to those obtained using completely dynamic modeling, despite considerable uncertainty in key exposure- and metabolic-model parameters. These findings suggest that, for PCE, risk estimation taking pharmacokinetics into account may be accomplished using a simple analytic approach.     

Causality Assessment of the Acute Health Complaints Reported in Association with Oxygenated Fuels

In some areas where oxygenated fuel programs have been implemented, there have been widespread complaints of non-specific health effects attributed to the gasoline. There are a number of hypotheses that can account for this apparent association. This paper examines the hypothesis that the use of oxy-fuel (either oxygenated gasoline or reformulated gasoline) results in exposure of the general population to one or more chemicals at concentrations that cause toxicologic injury. Although several oxygenates can be used in oxy-fuels, this analysis focuses on MTBE because it is the most widely used oxygenate and because the database of relevant toxicologic data is greatest for this oxygenate. The causal assessment is based on an evaluation of the qualitative and quantitative plausibility that oxygenated fuel-related exposures have toxicological effects, and the epidemiologic studies that directly test the hypothesis that the use of oxygenated fuels causes adverse health effects. The plausibility that chemical exposures related to oxy-fuel use cause toxicological effects is very low. This determination is based on consideration of the exposure-response and time-action profiles for relevant toxicological effects of MTBE in animals, experimental MTBE exposure studies in humans, and the possibility that the addition of MTBE to gasoline results in toxicologically significant qualitative and/or quantitative changes in gasoline-related exposures. Similarly, the epidemiologic studies of oxy-fuel exposed cohorts do not support a causal relationship between oxy-fuel use and adverse health effects. Although the data are insufficient to rule the possibility of unique sensitivity in a small segment of the population, the strength of the evidence and the availability of other more plausible explanations for the health complaints reported in association with oxy-fuels support a high degree of confidence in the conclusion that MTBE-containing oxygenated fuels are not the cause of acute toxicity in the general population.     

Evaluation of the Uncertainty in an Oral Reference Dose for Methylmercury Due to Interindividual Variability in Pharmacokinetics

An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 g/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 g/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 g/kg/day and an MRL of 0.3 g/kg/day.     

Probability Distributions for Showering and Bathing Water-Use Behavior for Various U.S. Subpopulations

It has been shown that bathroom-type water uses dominate personal exposure to water-borne contaminants in the home. Therefore, in assessing exposure of specific population groups to the contaminants in the water, understanding population water-use behavior for bathroom activities as a function of demographic characteristics is vital to realistic exposure estimates. In this article, shower and bath frequencies and durations are analyzed, presented, and compared for various demographic groups derived from analyses of the National Human Activities Pattern Survey (NHAPS) database and the Residential End Uses of Water Study (REUWS) database as well as from a review of current literature. Analysis showed that age and level of education significantly influenced shower and bath frequency and duration. The frequency of showering and bathing reported in NHAPS agreed reasonably well with previous studies; however, durations of these events were found to be significantly longer. Showering frequency reported in REUWS was slightly less than that reported for NHAPS; however, durations of showers reported in REUWS are consistent with other studies. After considering the strengths and weaknesses of each data set and comparing their results to previous studies, it is concluded that NHAPS provides more reliable frequency data, while REUWS provides more reliable duration data. The shower- and bath-use behavior parameters recommended in this article can aid modelers in appropriately specifying water-use behavior as a function of demographic group in order to conduct reasonable assessments of exposure to contaminants that enter the home via the water supply.     

An Analysis of the Health Benefits Associated with the Use of MTBE Reformulated Gasoline and Oxygenated Fuels in Reducing Atmospheric Concentrations of Selected Volatile Organic Compounds

To assess the health benefits gained from the use of cleaner burning gasoline, an analysis was conducted of changes in the atmospheric concentration of eight VOCs: acetaldehyde, benzene, 1,3-butadiene, ethylbenzene, formaldehyde, POM, toluene, and xylenes resulting from the use of reformulated gasoline and oxyfuel containing the additive MTBE. Modeled ambient air concentrations of VOCs were used to assess three seasonally-based scenarios: baseline gasoline compared to (a) summer MTBE:RFG, (b) winter MTBE:RFG, and (c) MTBE oxyfuel. The model predicts that the addition of MTBE to RFG or oxyfuel will decrease acetaldehyde, benzene, 1,3-butadiene and POM, but increase formaldehyde tailpipe emissions. The increased formaldehyde emissions, however, will be offset by the reduction of formaldehyde formation in the atmosphere from other VOCs. Using a range of plausible risk estimates, the analysis predicts a positive health benefit, i.e., a decline in cancer incidence associated with use of MTBE:RFG and MTBE oxyfuel. Using EPA cancer risk estimates, reduction in 1,3-butadiene exposure accounts for the greatest health benefit while reduction of benzene exposure accounts for the greatest health benefits based on alternative risk estimates. An analysis of microenvironment monitoring data indicates that most exposures to VOCs are significantly below levels of concern based on established margin-of-safety standards. The analysis does suggest, however, that health effects associated with short-term exposures to acetaldehyde and benzene may warrant further investigation.     

Predicted Infant Exposure to Tetrachloroethene in Human Breastmilk

Based on a variety of maternal occupational and residential inhalation exposure scenarios, estimates of infant exposure to the dry-cleaning solvent tetrachlorothylene (perchloroethylene, PCE) in breastmilk were made. Physiologically based pharmacokinetic (PBPK) modeling indicates that infants may be exposed to elevated levels of PCE in breastmilk due to their mothers' inhalation of PCE. The PBPK-predicted breastmilk PCE concentrations agree very well with measured concentrations, where available. Based on this analysis, infants may be exposed to this workplace chemical via breastmilk at doses corresponding to rather high levels of risk. Predicted breastmilk doses provide the infant with little margin of exposure to doses associated with adverse health effects. In addition, the estimated increased cancer risks associated with these infant exposures are large under certain exposure scenarios. The actual concentrations of PCE in breastmilk of exposed mothers can only be known with certainty if monitoring is conducted. Due to the widespread exposure potential, monitoring studies should be undertaken so that the appropriate risk management alternatives can be better evaluated.     

A Trichloroethylene Risk Assessment Using a Monte Carlo Analysis of Parameter Uncertainty in Conjunction with Physiologically-Based Pharmacokinetic Modeling

A Monte Carlo simulation is incorporated into a risk assessment for trichloroethylene (TCE) using physiologically-based pharmacokinetic (PBPK) modeling coupled with the linearized multistage model to derive human carcinogenic risk extrapolations. The Monte Carlo technique incorporates physiological parameter variability to produce a statistically derived range of risk estimates which quantifies specific uncertainties associated with PBPK risk assessment approaches. Both inhalation and ingestion exposure routes are addressed. Simulated exposure scenarios were consistent with those used by the Environmental Protection Agency (EPA) in their TCE risk assessment. Mean values of physiological parameters were gathered from the literature for both mice (carcinogenic bioassay subjects) and for humans. Realistic physiological value distributions were assumed using existing data on variability. Mouse cancer bioassay data were correlated to total TCE metabolized and area-under-the-curve (blood concentration) trichloroacetic acid (TCA) as determined by a mouse PBPK model. These internal dose metrics were used in a linearized multistage model analysis to determine dose metric values corresponding to 10^-6 lifetime excess cancer risk. Using a human PBPK model, these metabolized doses were then extrapolated to equivalent human exposures (inhalation and ingestion). The Monte Carlo iterations with varying mouse and human physiological parameters produced a range of human exposure concentrations producing a 10^-6 risk.     

Mechanistic Insights Aid the Search for CFC Substitutes: Risk Assessment of HCFC-123 as an Example

An international consensus on the need to reduce the use of chlorofluorocarbons (CFCs) and other ozone-depleting gases such as the halons led to the adoptions of the 1987 Montreal Protocol and Title VI of the 1990 Clean Air Act Amendments, "Protecting Stratospheric Ozone." These agreements included major provisions for reducing and eventually phasing out production and use of CFCs and halons as well as advancing the development of replacement chemicals. Because of the ubiquitous use and benefits of CFCs and halons, an expeditious search for safe replacements to meet the legislative deadlines is of critical importance. Toxicity testing and health risk assessment programs were established to evaluate the health and environmental impact of these replacement chemicals. Development and implementation of these programs as well as the structural-activity relationships significant for the development of the replacement chemicals are described below. A dose-response evaluation for the health risk assessment of the replacement chemical HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) is also presented to show an innovative use of physiologically based pharmacokinetic (PBPK) modeling. This is based on a parallelogram approach using data on the anesthetic gas halothane, a structural analog to HCFC-123. Halothane and HCFC-123 both form the same metabolite, trifluoroacetic acid (TFA), indicative of the same metabolic oxidative pathway attributed to hepatotoxicity. The parallelogram approach demonstrates the application of template model structures and shows how PBPK modeling, together with judicious experimental design, can be used to improve the accuracy of health risk assessment and to decrease the need for extensive laboratory animal testing.     

Chloroform Exposure and the Health Risk Associated with Multiple Uses of Chlorinated Tap Water

Recently, showers have been suspected to be an important source of indoor exposure to volatile organic compounds (VOC). The chloroform dose to an individual from showering was determined based on exhaled breath analysis. The postexposure chloroform breath concentration ranged from 6.0-21 micrograms/m3, while all corresponding background breath concentrations were less than 0.86 micrograms/m3. The internal dose from showering (inhalation plus dermal) was comparable to estimates of the dose from daily water ingestion. The risk associated with a single, 10-min shower was estimated to be 1.22 x 10(-4), while the estimated risk from daily ingestion of tap water ranged from 0.130 x 10(-4) to 1.80 x 10(-4) for 0.15 and 2.0 L, respectively. Since the estimates of chloroform risk from domestic water use for the three exposure routes--ingestion, inhalation, and dermal--are similar, all routes must be used to calculate the total risk when making policy decisions regarding the quality of the municipal water supply.