The Impact of Scaling Factor Variability on Risk-Relevant Pharmacokinetic Outcomes in Children: A Case Study Using Bromodichloromethane (BDCM).

Biotransformation rates extrapolated from in vitro data are used increasingly in human physiologically based pharmacokinetic (PBPK) models. This practice requires use of scaling factors, including microsomal content (mg of microsomal protein/g liver, MPPGL), enzyme specific content, and liver mass as a fraction of body weight (FVL). Previous analyses indicated that scaling factor variability impacts pharmacokinetic (PK) outcomes used in adult population dose-response studies. This analysis was extended to pediatric populations because large inter-individual differences in enzyme ontogeny likely would further contribute to scaling factor variability. An adult bromodichloromethane (BDCM) model (Kenyon, E. M., Eklund, C., Leavens, T. L., and Pegram, R. A. (2016a). Development and application of a human PBPK model for bromodichloromethane (BDCM) to investigate impacts of multi-route exposure. J. Appl. Toxicol. 36, 1095-1111) was re-parameterized for neonates, infants, and toddlers. Monte Carlo analysis was used to assess the impact of pediatric scaling factor variation on model-derived PK outcomes compared with adult findings. BDCM dose metrics were estimated following a single 0.05-liter drink of water or a 20-min bath, under typical (5 µg/l) and plausible higher (20 µg/l) BDCM concentrations. MPPGL, CYP2E1, and FVL values reflected the distribution of reported pediatric population values. The impact of scaling factor variability on PK outcome variation was different for each exposure scenario, but similar for each BDCM water concentration. The higher CYP2E1 expression variability during early childhood was reflected in greater variability in predicted PK outcomes in younger age groups, particularly for the oral exposure route. Sensitivity analysis confirmed the most influential parameter for this variability was CYP2E1, particularly in neonates. These findings demonstrate the importance of age-dependent scaling factor variation used for in vitro to in vivo extrapolation of biotransformation rates.

Health risk assessment of trihalomethanes mixtures from daily water-related activities via multi-pathway exposure based on PBPK model.

In this study, the concentrations of trihalomethanes (THMs) in tap water and direct drinking water were analyzed, and based on the human behavior patterns and building parameters, the concentrations of THMs in indoor air were simulated with the water-air concentration conversion model. In addition, concentrations of THMs in human tissues were predicted based on physiologically based pharmacokinetic (PBPK) model, and the health risk of THMs for participants were estimated. Furthermore, the carcinogenic risk of mixtures according to the method proposed by USEPA and PBPK model based method were calculated and compared. The concentrations of chloroform, bromodichloromethane, dibromochloromethane and bromoform in tap water were 11.28-16.21, 4.83-6.28, 0.81-1.32 and 0.08-0.21 µg/L, and those in direct drinking water were 3.29-6.88, 0.35-0.47, 0.03-0.08 and 0.04-0.08 µg/L, respectively. The results of water-air concentration conversion model demonstrated that pollutants in air had a strong correlation with water-related activities. Multi-pathway PBPK model showed that THMs concentrations in liver, kidney and richly perfused tissue were higher than those in other tissues. The results of risk assessment showed that the mean risk levels of mixtures were 1.69 × 10-4 and 1.72 × 10-4 calculated by the USEPA recommended method and PBPK based method, which seriously exceeded the acceptable level. TCM and BDCM were the major risk factors, and inhalation was the main exposure route of THMs.

The impact of variation in scaling factors on the estimation of internal dose metrics: a case study using bromodichloromethane (BDCM).

A rate for hepatic metabolism (Vmax) determined in vitro must be scaled for in vivo use in a physiologically based pharmacokinetic (PBPK) model. This requires the use of scaling factors such as mg of microsomal protein per gram of liver (MPPGL) and liver mass (FVL). Variation in MPPGL and FVL impacts variation in Vmax, and hence PBPK model-derived estimates of internal dose used in dose response analysis. The impacts of adult human variation in MPPGL and FVL on estimates of internal dose were assessed using a human PBPK model for bromodichloromethane (BDCM), a water disinfection byproduct, for multiple internal dose metrics for two exposure scenarios (single 0.25 liter drink of water or 10 min shower) under plausible (5 µg/L) and high level (20 µg/L) water concentrations. For both concentrations, all internal dose metrics were changed less than 5% for the showering scenario (combined inhalation and dermal exposure). In contrast, a 27-fold variation in area under the curve (AUC) for BDCM in venous blood was observed at both oral exposure concentrations, whereas total amount of BDCM metabolized in liver was relatively unchanged. This analysis demonstrates that variability in the scaling factors used for in vitro to in vivo extrapolation (IVIVE) for metabolic rate parameters can have a significant route-dependent impact on estimates of internal dose under environmentally relevant exposure scenarios. This indicates the need to evaluate both uncertainty and variability for scaling factors used for IVIVE.

Using physiologically based pharmacokinetic models to estimate the health risk of mixtures of trihalomethanes from reclaimed water.

To estimate the health risk of mixture of trihalomethanes (THMs) from reclaimed water during toilet flushing, the interaction-based Hazard Index (HI(interaction-based)) and the mixture carcinogenic risk (CRM) according to tissue dose were conducted through the integrated use of both the exposure concentrations model and the physiologically based pharmacokinetic (PBPK) model of THMs. Monte Carlo simulations were employed to implement the probabilistic risk analysis and sensitivity analysis. Nine samples were analyzed, which were collected from J Water Reclamation Plant (JWRP) in Tianjin of China. The results indicated that the mean HI(interaction-based) (=0.85) was lower than the acceptable risk level (=1). The probability that the HI(interaction-based) exceeded the acceptable risk level is 22.97%. For carcinogenic risk, the CRM ranges from 9.41×10(-7) to 3.54×10(-5), with a mean of 5.49×10(-6). Moreover, the probability of exceeding the acceptable risk level (1×10(-6)) is near 100%. And the values of HI(interaction-based) from sample no. 1, 5, and 7 exceeded 1, while the values of CRM for all samples exceeded 1×10(-6). Consequently, the reclaimed water used for flushing toilets should be paid more attention, though non-carcinogenic effect is relatively small. Furthermore, the concentrations of DBCM had greater impact on both the carcinogenic and non-carcinogenic risk based on sensitivity analysis.

Heated indoor swimming pools, infants, and the pathogenesis of adolescent idiopathic scoliosis: a neurogenic hypothesis.

BACKGROUND: In a case-control study a statistically significant association was recorded between the introduction of infants to heated indoor swimming pools and the development of adolescent idiopathic scoliosis (AIS). In this paper, a neurogenic hypothesis is formulated to explain how toxins produced by chlorine in such pools may act deleteriously on the infant's immature central nervous system, comprising brain and spinal cord, to produce the deformity of AIS. PRESENTATION OF THE HYPOTHESIS: Through vulnerability of the developing central nervous system to circulating toxins, and because of delayed epigenetic effects, the trunk deformity of AIS does not become evident until adolescence. In mature healthy swimmers using such pools, the circulating neurotoxins detected are chloroform, bromodichloromethane, dibromochloromethane, and bromoform. Cyanogen chloride and dichloroacetonitrile have also been detected. TESTING THE HYPOTHESIS: In infants, the putative portals of entry to the blood could be dermal, oral, or respiratory; and entry of such circulating small molecules to the brain are via the blood-brain barrier, blood-cerebrospinal fluid barrier, and circumventricular organs. Barrier mechanisms of the developing brain differ from those of adult brain and have been linked to brain development. During the first 6 months of life cerebrospinal fluid contains higher concentrations of specific proteins relative to plasma, attributed to mechanisms continued from fetal brain development rather than immaturity. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis can be tested. If confirmed, there is potential to prevent some children from developing AIS.

Evaluation of the impact of the exposure route on the human kinetic adjustment factor.

The objective of this study was to assess the impact of the exposure route on the human kinetic adjustment factor (HKAF), for which a default value of 3.16 is used in non-cancer risk assessment. A multi-route PBPK model was modified from the literature and used for computing the internal dose metrics in adults, neonates, children, elderly and pregnant women following three route-specific scenarios to chloroform, bromoform, tri- or per-chloroethylene (TCE or PERC). These include 24-h inhalation exposure, body-weight adjusted oral exposure and 30 min dermal exposure to contaminated drinking water. Distributions for body weight (BW), height (BH) and hepatic cytochrome P450 2E1 (CYP2E1) content were obtained from the literature, whereas model parameters (flows, volumes) were calculated from BW and BH. Monte Carlo simulations were performed and the HKAF was calculated as the ratio of the 95th percentile value of internal dose metrics in subpopulation to the 50th percentile value in adults. On the basis of the area under the parent compound's arterial blood concentration vs time curve (AUC(pc)), highest HKAFs were obtained in neonates for every scenario considered, and were the highest for bromoform (range: 3.6-7.4). Exceedance of the default value based on AUC(PC) was also observed for an oral exposure to chloroform in neonates (4.9). In all other cases, HKAFs remained below the default value. Overall, this study has pointed out the dependency of the HKAF on the exposure route, dose metrics and subpopulation considered, as well as characteristics of the chemicals investigated.

Biomonitoring Equivalents (BE) dossier for trihalomethanes.

Measurements of whole blood concentrations of trihalomethanes (THMs) have been reported in persons in the general population. Risk assessments based on administered doses of THMs have been conducted for both cancer and non-cancer health endpoints by the US Environmental Protection Agency; however, no health-based standards exist for interpreting measured blood concentrations of THMs. Existing physiologically based pharmacokinetic models for laboratory rats, dogs, and humans were used to estimate the average blood concentrations consistent with the points of departure, reference doses (RfDs), and, where applicable, cancer potency estimates to provide biomonitoring equivalents (BEs) for these exposure guidance values. The models were also used to characterize the short term variations in blood concentrations that could result from various exposure regimens, even when exposures remain consistent with the underlying RfDs. The BE values derived in this exercise can be used as one component of a screening-level assessment of future population biomonitoring THM data.

Disposition of bromodichloromethane in humans following oral and dermal exposure.

Exposure to bromodichloromethane (BDCM), one of the most prevalent disinfection byproducts in drinking water, can occur via ingestion of water and by dermal absorption and inhalation during activities such as bathing and showering. The objectives of this research were to assess BDCM pharmacokinetics in human volunteers exposed percutaneously and orally to (13)C-BDCM and to evaluate factors that could affect disposition of BDCM. Among study subjects, CYP2E1 activity varied fourfold; 20% had the glutathione S-transferase theta 1-1 homozygous null genotype; and body fat ranged from 7 to 22%. Subjects were exposed to (13)C-BDCM in water (target concentration of 36 mug/l) via ingestion and by forearm submersion. Blood was collected for up to 24 h and analyzed for (13)C-BDCM by solid-phase microextraction and high-resolution GC-MS. Urine was collected before and after exposure for mutagenicity determinations in Salmonella. After ingestion (mean dose = 146 ng/kg), blood (13)C-BDCM concentrations peaked and declined rapidly, returning to levels near or below the limit of detection (LOD) within 4 h. The T(max) for the oral exposure ranged from 5 to 30 min, and the C(max) ranged from 0.4 to 4.1 ng/l. After the 1 h dermal exposure (estimated mean dose = 155 ng/kg), blood concentrations of (13)C-BDCM ranged from 39 to 170 ng/l and decreased to levels near or below the LOD by 24 h. Peak postdose urine mutagenicity levels that were at least twice that of the predose mean level occurred in 6 of 10 percutaneously exposed subjects and 3 of 8 orally exposed subjects. These results demonstrate a highly significant contribution of dermal absorption to circulating levels of BDCM and confirm the much lower oral contribution, indicating that water uses involving dermal contact can lead to much greater systemic BDCM doses than water ingestion. These data will facilitate development and validation of physiologically based pharmacokinetic models for BDCM in humans.

Effects of bromodichloromethane on ex vivo and in vitro luteal function and bromodichloromethane tissue dosimetry in the pregnant F344 rat.

Bromodichloromethane (BDCM), a drinking water disinfection by-product, causes pregnancy loss, i.e. full-litter resorption, in F344 rats when treated during the luteinizing hormone (LH)-dependent period. This effect is associated with reduced maternal serum progesterone (P) and LH levels, suggesting that BDCM disrupts secretion of LH. To test the hypothesis that BDCM also affects luteal responsiveness to LH, we used ex vivo and in vitro approaches. For the ex vivo study (i.e., in vivo exposure followed by in vitro assessment), dams were dosed by gavage on gestation days (GD) 6-9 (plug day=GD 0) at 0 or 100 mg/kg/d. One hour after the GD-9 dose, rats were killed, blood was collected, and tissue concentrations of BDCM were assessed. Corpora lutea (CL) were incubated with or without hCG, an LH agonist, to stimulate P secretion. For the in vitro study, CL were pooled from untreated F344 rats on GD 9 and cultured with BDCM at 0, 0.01, 0.10 or 3.0 mM. BDCM was found at highest concentrations in adrenal, ovarian, adipose, and hypothalamic tissues. BDCM treatment decreased serum P and LH levels in vivo. Ex vivo, however, BDCM-exposed CL showed >2-fold increases in P secretion relative to controls. Both control and BDCM-exposed CL displayed a 2.4-fold increase in P secretion in response to hCG challenge. In contrast, in vitro exposures reduced CL responsiveness in a dose-related fashion while baseline levels were unaffected. It is unclear if the ex vivo 'rebound' reflects the removal of the CL from a possible direct inhibitory influence of BDCM, or a response to diminished LH stimulation in vivo. Thus, these data suggest that BDCM disrupts pregnancy in F344 rats via two modes: disruption of LH secretion, and disruption of the CL's ability to respond to LH.

Reverse dosimetry: interpreting trihalomethanes biomonitoring data using physiologically based pharmacokinetic modeling.

Biomonitoring data provide evidence of exposure of environmental chemicals but are not, by themselves, direct measures of exposure. To use biomonitoring data in understanding exposure, physiologically based pharmacokinetic (PBPK) modeling can be used in a reverse dosimetry approach to assess a distribution of exposures possibly associated with specific blood or urine levels of compounds. Reverse dosimetry integrates PBPK modeling with exposure pattern characterization, Monte Carlo analysis, and statistical tools to estimate a distribution of exposures that are consistent with biomonitoring data in a population. The present study used an existing PBPK model for chloroform as a generic framework to develop PBPK models for other trihalomethanes (THMs). Using Monte Carlo sampling techniques, probabilistic information about pharmacokinetics and exposure patterns was included to estimate distributions of THMs concentrations in blood in relation to various exposure patterns in a diverse population. In addition, the possibility of inhibition of hepatic metabolism among THMs was evaluated under the scenarios of household exposure. These studies demonstrated how PBPK modeling can be used as a tool to estimate a population distribution of exposures that could have resulted in particular biomonitoring results. When toxicity level is known, this tool can also be used to estimate proportion of population above levels associated with health risk.

Chlorination byproducts, their toxicodynamics and removal from drinking water.

No doubt that chlorination has been successfully used for the control of water borne infections diseases for more than a century. However identification of chlorination byproducts (CBPs) and incidences of potential health hazards created a major issue on the balancing of the toxicodynamics of the chemical species and risk from pathogenic microbes in the supply of drinking water. There have been epidemiological evidences of close relationship between its exposure and adverse outcomes particularly the cancers of vital organs in human beings. Halogenated trihalomethanes (THMs) and haloacetic acids (HAAs) are two major classes of disinfection byproducts (DBPs) commonly found in waters disinfected with chlorine. The total concentration of trihalomethanes and the formation of individual THM species in chlorinated water strongly depend on the composition of the raw water, on operational parameters and on the occurrence of residual chlorine in the distribution system. Attempts have been made to develop predictive models to establish the production and kinetics of THM formations. These models may be useful for operational purposes during water treatment and water quality management. It is also suggested to explore some biomarkers for determination of DBP production. Various methods have been suggested which include adsorption on activated carbons, coagulation with polymer, alum, lime or iron, sulfates, ion exchange and membrane process for the removal of DBPs. Thus in order to reduce the public health risk from these toxic compounds regulation must be inforced for the implementation of guideline values to lower the allowable concentrations or exposure.

Development of physiologically based toxicokinetic models for improving the human indoor exposure assessment to water contaminants: trichloroethylene and trihalomethanes.

Generally, ingestion is the only route of exposure that is considered in the risk assessment of drinking water contaminants. However, it is well known that a number of these contaminants are volatile and lipophilic and therefore highly susceptible to being absorbed through other routes, mainly inhalation and dermal. The objective of this study was to develop physiologically based human toxicokinetic (PBTK) models for trihalomethanes (THM) and trichloroethylene (TCE) that will facilitate (1) the estimation of internal exposure to these chemicals for various multimedia indoor exposure scenarios, and (2) consideration of the impact of biological variability in the estimation of internal doses. Five PBTK models describing absorption through ingestion, inhalation and skin were developed for these contaminants. Their concentrations in ambient air were estimated from their respective tap water concentrations and their physicochemical characteristics. Algebraic descriptions of the physiological parameters, varying as a function of age, gender and diverse anthropometric parameters, allow the prediction of the influence of interindividual variations on absorbed dose and internal dosimetry. Simulations for various scenarios were done for a typical human (i.e., 70 kg, 1.7 m) as well as for humans of both genders varying in age from 1 to 90 years. Simulations show that ingestion contributes to less than 50% of the total absorbed dose or metabolized dose for all chemicals. This contribution to internal dosimetry, such as maximal venous blood concentrations (Cmax) and the area under the venous blood concentration time curve (AUC), decreases markedly (e.g., as low as 0.9% of Cmax for bromodichloromethane). The importance of this contribution varies mainly as a function of shower duration. Moreover, model simulations indicate that multimedia exposure is more elevated in children than adults (i.e., up to 200% of the adult internal dose). The models developed in this study allow characterization of the influence of the different routes of exposure and an improved estimation of the realistic multimedia exposure to volatile organic chemicals present in drinking water. Hence, such models will greatly improve health risk assessment for these chemicals.

Evaluation of the influence of chloroacetic acids on the pharmacokinetics of trihalomethanes in the rat.

Chloroacetic acids (monochloroacetic acid [MCA], dichloroacetic acid [DCA], and trichloroacetic acid [TCA]) and trihalomethanes (THMs: chloroform [CHCl(3)], bromodichloromethane [BDCM], dibromochloromethane [DBCM], and bromoform [TBM]) are common by-products of the chlorination of drinking water. The purpose of this study was to evaluate the influence of chloroacetic acids on the pharmacokinetics of trihalomethanes in the male Sprague-Dawley rat. In the first series of studies, groups of 5 animals were given, by intravenous injections, a single dose of 0.125 mmol/kg of one of the four THMs. Additional groups received a binary mixture containing 0.125 mmol/kg of a THM plus 0.125 mmol/kg of a chloroacetic acid. The venous blood concentrations of unchanged THMs were measured by headspace gas chromatography from 5 min to 6 h postadministration. The areas under the blood concentration versus time curves (AUCs) of CHCl(3), BDCM, and DBCM were increased by a factor of 3.5, 1.6, and 2, respectively, by coadministration of TCA. DCA coadministration resulted in an increase in the AUC of DBCM (x2.5) and TBM (x1.3), whereas MCA modified the Cmax (x1.5) and AUC (x1.8) of BDCM and the AUC of DBCM (x2.5). In the second series of experiments, animals received either a single dose of 0.03125 mmol/kg of one of the four THMs, a mixture containing 0.03125 mmol/kg of each of the four THMs (total dose = 0.125 mmol/kg), or a mixture containing 0.03125 mmol/kg of each of the four THMs plus 0.125 mmol/kg of either TCA or DCA. Results indicated that the AUCs of CHCl(3), BDCM, DBCM, and TBM were increased during coadministration compared to single administrations (+2.5-fold). Combined administration of the four THMs with TCA, and not DCA, resulted in an increase of the AUCs of THMs (CHCl(3): x11.7; BDCM, DBCM, and TBM: x3.9) and an increase in the Cmax of CHCl(3) (x1.9). Overall, these results indicate that, at the dose levels tested in this study, TCA alters the blood concentration profiles of THMs.

Percutaneous absorption of trihalomethanes, haloacetic acids, and haloketones.

Bathing in chlorinated drinking water causes significant exposure to potentially toxic disinfection by-products (DBPs). In the present studies, we measured the permeation coefficients (K(p)) of three important classes of DBPs, trihalomethanes (THMs), haloketones (HKs), and haloacetic acids (HAAs), in aqueous solution across human skin using in vitro diffusion chambers. Linear mixed-effects model was utilized to calculate the steady-state permeability coefficients. The permeability coefficients of THMs ranged from 0.16 to 0.21 cm/h when the donor solution was at 25 degrees C. Bromoform had the highest K(p) value, while chloroform was the least permeable through the skin. THMs were approximately 10 times more permeable than HKs, while the permeability of HAAs through the skin was very low (1 to 3 x 10(-3) cm/h, pH 7). The permeability of HKs tripled as the temperature was increased from room temperature (20 degrees C) to bathing temperature (40 degrees C). A direct relationship was found between the permeability of THMs, but not HKs and HAAs, and their octanol/water partition coefficients. The dermal dose from daily bathing activities was approximated for an average adult using U.S. EPA recommended methods and found to be 40-70% of the daily ingestion dose for the THMs, 10% of the ingestion dose for HKs, and an insignificant percentage of the ingestion dose for the HAAs. In addition to ingestion, dermal absorption is an important route of exposure to THMs and HKs and must be considered in models of risk assessment.

Quantitative evaluation of bromodichloromethane metabolism by recombinant rat and human cytochrome P450s.

We report quantitative estimates of the parameters for metabolism of bromodichloromethane (BDCM) by recombinant preparations of hepatic cytochrome P450s (CYPs) from rat and human. Earlier work identified CYP2E1, CYP2B1/2 and CYP1A2 as activating enzymes necessary for hepatotoxicity in rat. In order to extend an existing PBPK model for rat to include a capability for extrapolation to humans, it is necessary to evaluate quantitatively the principal metabolic pathways in both species. We have conducted in vitro experiments using recombinant preparations of the three rat CYP isoenzymes mentioned above and for CYP2C11 and CYP3A1 as well. Similar experiments have been performed with human recombinant isoenzymes for CYP2E1, CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP3A4. Results indicate that the principal metabolizing enzymes in rat are those identified previously, CYP2E1, CYP2B1/2 and CYP1A2. CYP3A1 may also have some activity. In human, CYP2E1, CYP1A2 and CYP3A4 show substantial activity, and CYP2A6 also measurably metabolizes BDCM. In both species, CYP2E1 is the low K(m) isoenzyme, with K(m) approximately 27-fold lower than those for the isoenzymes with the next lowest K(m). In addition, the metabolic parameters, K(m) and k(cat), for rat and human CYP2E1 were nearly identical. The metabolic parameters for CYP1A2, the only other isoenzyme active in both species, were not similar across species. In addition, calculations based on the kinetic constants obtained are compared to results from two in vivo experiments to show that the in vitro kinetic data is relevant to in vivo exposures. We conclude that although several CYPs metabolize BDCM, at low concentration/exposure, BDCM metabolism is dominated by CYP2E1 in both rat and human, but that other isoenzymes can be important at higher concentrations. We further conclude that the kinetic data are consistent with existing in vivo results.

Kinetics of bromodichloromethane metabolism by cytochrome P450 isoenzymes in human liver microsomes.

The kinetic constants for the metabolism of bromodichloromethane (BDCM) by three cytochrome P450 (CYP) isoenzymes have been measured in human liver microsomes. The three CYP isoenzymes, CYP2E1, CYP1A2 and CYP3A4, have been identified previously as important in the metabolism of this compound. To measure the constants for each isoenzyme, enzyme-specific inhibitory antibodies were used to block the activities for two of the three isoenzymes. CYP2E1 was found to have the lowest K(m), 2.9 microM, and the highest catalytic activity, k(cat). The K(m) for the other isoenzymes, CYP1A2 and CYP3A4, were about 60 microM with lower values of k(cat). Apparent kinetic constants obtained from two microsomal samples that were not inhibited were consistent with these results. In addition, 11 human microsome samples characterized for 10 CYP activities were correlated with the metabolism of 9.7 microM BDCM by each sample; statistical analysis showed a correlation with CYP2E1 activity only. This result is consistent with the finding that CYP2E1 is the only isoenzyme with a K(m) lower than the BDCM concentration used. The kinetic constants obtained from the inhibited microsomes were compared to similar results from recombinant human isoenzyme preparations containing only one CYP isoenzyme. The results for CYP2E1 were very similar, while the results for CYP1A2 were somewhat less similar and there was a substantial divergence for CYP3A4 in the two systems. Possible reasons for these differences are differing levels of CYP reductase and/or differing makeup of the membrane lipid environment for the CYPs. Because of the low levels of BDCM exposure from drinking water, it appears likely that CYP2E1 will dominate hepatic CYP-mediated BDCM metabolism in humans.

Partition coefficients for the trihalomethanes among blood, urine, water, milk and air.

Chloroform, bromodichloromethane, chlorodibromomethane, and bromoform comprise the trihalomethanes, a group of widespread and mildly lipophilic compounds that result from water chlorination and other sources. Many animal studies show the chronic toxicity and carcinogenicity of these compounds, and recent work has demonstrated the importance of both ingestion and inhalation exposure pathways. This study presents partition coefficients describing the equilibrium among biological compartments (air, water, blood, milk, urine) for the four THMs based on results of headspace gas chromatographic analyses performed under equilibrium conditions and at 37 degrees C. The calculated partition coefficients ranged from 2.92 to 4.14 for blood/water, 1.54-2.85 for milk/blood, and 3.41-4.93 for blood/urine, with the lowest being chloroform and the highest being bromoform. Both human and cow milk were tested, with similar results. The available samples of human milk may not fully account for differences in lipid content and possibly other factors that affect estimates of partition coefficients. Simultaneous measurements of milk and blood in exposed individuals are suggested to confirm laboratory results. Partition coefficients are predicted using the octanol-air partition coefficient, also measured in this study, and the octanol-water partition coefficient. Results are similar to literature estimates for liquid/air partitioning of chloroform and chlorodibromomethane, but they differ from predictions based on hydrophobicity and lipid content. High correlations between the derived partitioned coefficients and the molecular structure (number of Br atoms) and physical properties (molecular weight and boiling point) are found for these analogous chemicals. In humans, THMs are both stored and metabolized with relatively rapid clearance rates. The derived partition coefficients can help to interpret results of biological monitoring and predict the potential for the accumulation and transfer of chemicals, specifically by the application of physiologically-based pharmacokinetic models. THM exposures to potentially susceptible populations, e.g. nursing infants, can be predicted using either such models.

Biodisposition of dibromoacetic acid (DBA) and bromodichloromethane (BDCM) administered to rats and rabbits in drinking water during range-finding reproduction and developmental toxicity studies.

Dibromoacetic acid (DBA) and bromodichloromethane (BDCM), by-products of chlorine disinfection of water, were provided in drinking water in range-finding reproductive/developmental toxicity studies (rats) and a developmental toxicity study (BDCM) in rabbits. Studies included absorption and biodisposition of DBA and BDCM, including passage into placentas, amniotic fluid, fetuses (rats and rabbits), or milk (rats). The DBA and BDCM range-finding reproductive/developmental toxicity studies each included 50 Sprague-Dawley rats/sex/group. DBA (0, 125, 250, 500, or 1000 ppm) or BDCM (0, 50, 150, 450, or 1350 ppm) was provided in drinking water 14 days premating through gestation and lactation (63 to 70 days). The developmental toxicity range-finding study included 25 time-mated New Zealand white rabbits/group given 0, 50, 150, 450, or 1350 ppm BDCM in drinking water on gestation days (GDs) 6 through 29. Satellite groups (6 male, 17 female rats/group/study and 4 rabbits/group) were used for bioanalytical sampling. Rats and rabbits had exposure-related reduced water consumption caused by apparent taste aversion to DBA or BDCM, especially in the parental animals at the two highest exposure levels (500 and 1000 ppm DBA; 450 and 1350 ppm BDCM). Female rats consumed slightly higher mg/kg/day doses of DBA than male rats, especially during gestation and lactation; weanling rats consumed the highest mg/kg/day doses. DBA produced detectable and quantifiable concentrations in plasma, placentas, amniotic fluid, and milk. Plasma samples confirmed that rats drink predominately during the dark; this drinking pattern, not accumulation, produced detectable plasma concentrations for 18 to 24 hours/day. No quantifiable concentrations of BDCM occurred in plasma, placentas, amniotic fluid, or milk, suggesting that BDCM is rapidly degraded or metabolized in vivo. DBA (500 and 1000 ppm, rats) and BDCM (450 and 1350 ppm, rats and rabbits) produced secondary toxicity in the parental generation by reducing water consumption, which caused severe exposure-related apparent dehydration, reduced feed intake and weight gain. Reproductive and developmental parameters were essentially unaffected (mating possibly reduced [DBA at 1000 ppm]; exposure-related decreases in body weights of pups secondary to reduced water and feed consumption [DBA at 250, 500, and 1000 ppm; BDCM at 150, 450, and 1350 ppm]). No effects on development of rabbit fetuses occurred at BDCM concentrations as high as 1350 ppm. Results from these preliminary studies, in which DBA and BDCM were provided in the drinking water at concentrations thousands of times higher than those to which humans are exposed, suggest that neither DBA nor BDCM are reproductive/developmental risks for humans.