Dermal uptake of chloroform and haloketones during bathing

Release time:2016-05-09

aThe Cancer Institute of New Jersey, Environmental and Occupational Health Sciences Institute, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersy USA
Correspondence: C.P. Weisel, Environmental and Occupational Health Sciences Institute, UMDNJ-Robert Wood Johnson Medical School, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA. Tel: +1-732-445-0154; Fax: +1-732-445-0116;
Received 27 August 2003; Accepted 18 June 2004; Published online 18 August 2004.

Dermal contact with some organic disinfection by-products (DBPs) such as trihalomethanes in chlorinated drinking water has been established to be an important exposure route. We evaluated dermal absorption of two haloketones (1,1-dichloropropanone and 1,1,1-trichloropropanone) and chloroform while bathing, by collecting and analyzing time profiles of expired breath samples of six human subjects during and following a 30-min bath. The DBP concentrations in breath increased towards a maximum concentration during bathing. The maximum haloketone breath concentration during dermal exposure ranged from 0.1 to 0.9 g / m3, which was approximately two orders of magnitude lower than the maximum chloroform breath concentration during exposure. Based on a one-compartment model, the in vivo permeability of chloroform, 1,1-dichloropropanone, and 1,1,1-trichloropropanone were approximated to be 0.015, 7.5  10- 4, and 4.5  10- 4 cm / h, respectively. Thus, haloketones are much less permeable across human skin under normal bathing conditions than is chloroform. These findings will be useful for future assessment of total human exposure and consequent health risk of these DBPs.

dermal absorption, disinfection by-products, haloketones, bath, skin permeability, expired air

Trihalomethanes, haloacetic acids, haloacetonitriles, and haloketones (HKs) are the most important classes of disinfection by-products (DBPs) based on concentration in chlorinated drinking water (Quimby et al., 1980; Christman et al., 1983; Krasner et al., 1989; Steven et al., 1990). The most prevalent HKs in drinking water are 1,1-dichloropropanone (DCP) and 1,1,1-trichloropropanone (TCP) (Meier et al., 1985). Although the concentrations of the two volatile HKs are an order of magnitude lower than those of trihalomethanes and haloacetic acids (Steven et al., 1990; LeBel et al., 1997; Simpson and Hayes, 1998), both of the compounds are carcinogenic and mutagenic in mice (Bull and Robinson, 1985). Epidemiological research suggests that exposure to DBPs in drinking water may be associated with a variety of cancers (Cantor et al., 1998;Hildesheim et al., 1998).

Human exposure to the water pollutants including DBPs in drinking water is multiroute (Jo et al., 1990). Dermal absorption of some lipophilic contaminants in water has been shown to be a significant contributor to the total exposure (Shatkin and Brown, 1991; Wallace, 1997). Plasma chloroform concentrations (Aggazzotti et al., 1990) and chloroform concentrations in expired breath (Aggazzotti et al., 1993; Levesque et al., 1994; Weisel and Shepard, 1994;Lindstrom et al., 1997) have been used as biomarkers to evaluate the body burden of chloroform for swimmers. Gordon et al., (1998) recently utilized real-time breath measurement technology to investigate dermal-only exposure to chloroform while bathing. We measured breath concentrations of chloroform, DCP, and TCP during and following inhalation exposure to these compounds (Xu and Weisel, 2004). The exhaled breath concentrations were analyzed by a thermal desorption system coupled with GC / ECD, which provided a detection limit of approximately 0.02 g / m3 for these DBPs.

To date, most studies only focused on dermal exposure to trihalomethanes, particularly chloroform. There is little information reported for dermal absorption of the other DBPs in chlorinated drinking water including HKs. By using in vitromethods, we determined the permeability of the HKs across human skin (Xu et al., 2002). This in vitro study suggested that DCP and TCP penetrate human skin within a few minutes. Therefore, dermal exposure route needs to be considered in the models of risk assessment of these DBPs.

In vivo measurements of dermal exposure may give more realistic estimation of the body burden contributed by the dermal route. In the present study, we measured the exhaled breath concentrations of DCP and TCP for human subjects during and following dermal exposure to these compounds while bathing and evaluated the significance of dermal absorption of the DBPs. Chloroform was included as a reference compound.

Materials and methods

Human Subjects
Six human volunteers, three males and three females, participated in the dermal exposure study. Table 1 lists the characteristics of the volunteers. Blood volumes, alveolar respiration rates, and body surface areas of the volunteers were estimated based on the height and body the weight of each individual (Table 1). The volunteers were healthy adults who did not have any respiratory or skin diseases, nor were pregnant at the time of the experiment. The volunteers were asked not to consume any water, drinks, or food that contained chlorinated water starting 1 day prior to the participation. To facilitate this, the volunteers were provided bottled water to drink and for food preparation. The volunteers were also asked to avoid showering, bathing, or swimming 1 day before the experiment. The study protocol was reviewed and approved by the Institutional Review Board for Human Subjects of the University of Medicine and Dentistry of New Jersey. Informed consent was obtained from each subject.

Table 1 - Subject characteristics.

Dermal Exposure and Breath Sampling During Bathing

A bathtub was filled with 40 gallons (approximately 530 l) of charcoal-purified water and the temperature was adjusted to 381°C. Approximately 15 mg of the HKs (DCP and TCP) and 20 mg of chloroform were dissolved into 10-ml deionized water in a capped glass tube by ultrasonication for half an hour. The DBP water solution was then added into the bath tub and well mixed with the tub water to obtain a concentration of 25 g / l for the haloketones and 40 g / l for chloroform. The selected HK concentration might represent a realistic upper limit of HKs that would be present in a poorly controlled water system (Clemens and Scholer, 1992; US EPA, 1996; Kim et al., 2002), whereas the chloroform concentration is well below the upper-end concentrations found in drinking water systems or swimming pools (Aggazzotti et al., 1990, 1993; Weisel and Shepard, 1994). Before entering the bathroom, the subject changed into a swimsuit and put on a mouth-breathing face mask (7930 series, Hans Rudolph, Inc., Kansas City, MO, USA) which was prefitted to the subject. Ultimate Seal Gels and Comfort Seal foam (Hans Rudolph, Inc.) were used to ensure a proper fit of the mask to the face of individual subjects. The face mask was equipped with a two-way nonbreathing valve. The subject inhaled the air through the one-way valve of the inhalation port which was attached to a charcoal filter to provide a purified air supply, preventing inhalation exposure to the volatile DBPs. Once the subject stepped into the bathtub, a polyethylene storage tube which provided a sufficient volume to store the breath was attached to the exhalation port of the face mask by a Teflon interface connector. The subject exhaled the expired air through a one-way valve in the exhalation port. The expired air in the polyethylene tube was drawn onto a Tenax trap through the sampling port located at the Teflon interface connector with a personal air sampling pump (SKC, Inc., Eighty Four, PA, USA) at a flow rate of approximately 1 l / min for 2 min. The flow rate was measured during the sampling procedure with a Dry-Cal primary calibrator (SKC. Inc.) in the sampling train. The subject was submerged in the water, except for the head, for 30 min and breath samples were collected at 5, 10, 15, 20, 25, and 28 min during the exposure.

Pre- and Postexposure Breath Sampling

Two breath samples were collected with an alveolar-breath sampler at 5 and 10 min before exposure to determine the background of DBPs in the breath of the subject (Raymer et al., 1990). After the exposure, the subject walked out of the hot tub without taking off the face mask and continued to breathe purified air. After the subject dried and dressed himself / herself, breath samples were collected with the alveolar-breath sampler at the time points of 5, 10, 15, 30, 45, 60, and 120 min after the exposure. The sampling duration for the pre- and postexposure samples were 2 min. Tenax traps were used for collection of the DBPs in the exhaled breath. The breath samples were analyzed using the thermal desorption / GC / ECD system described previously (Xu et al., 2002).

Collection and Analysis of Water Samples

Four water samples were collected, one sample before the subject walked into the bathtub, two samples at 10 and 20 min during exposure, and a final sample immediately after the exposure. The water samples were analyzed by GC / ECD after MTBE extraction (Xu et al., 2002).

Data Analysis

The stratum corneum is considered to be the primary barrier to dermal transport of chemicals across the skin, with epidermis and dermis having insignificant resistance to penetration by chemicals (Scheuplein, 1971). Usually, the stratum corneum is modeled as a homogeneous membrane (Roy et al., 1996; Pirot et al., 1997). The passive diffusion of a chemical through the stratum corneum is represented by Fick's second law of diffusion as (Crank, 1975):

where Csc(x,t) is the concentration of the chemical in the stratum corneum at distance x at time t and Dsc is the diffusion coefficient of the chemical in the stratum corneum. According to the exposure scenario described in this study, the boundary conditions at the skin / water (x=0) and skin / blood (x=hsc) interfaces are defined by the partitioning of the chemical between bath water and the stratum corneum and the partitioning between the blood and the skin, respectively

where Psc / w is the skin-to-water partition coefficient, Cw is the chemical water concentration in the hot tub, Psk / blood is the skin-to-blood partition coefficient,Cblood is the blood concentration, and hsc is the effective pathlength of the skin barrier.
Assuming a zero initial chemical concentration in the stratum corneum, the initial condition for the parabolic partial differential equation is

There are no simple analytical solutions for the diffusion equation under the initial and boundary conditions. Assuming a constant water concentration and negligible changes in the blood concentration at steady state, the accumulative amount (Min) of the chemical penetrating through a unit area of the skin has been given as (Parry et al., 1990)

where Jx=hss is the steady-state mass flux through the skin and Kp is the permeability coefficient of the chemical.

The one-compartment pharmacokinetic model developed by Wallace et al., (1993) can be used to describe the lung excretion of volatile compounds assuming that the exhaled alveolar air equilibrates with the blood according to the blood / air partition coefficient and the clearance of chemicals in the blood compartment follows a first-order kinetics (Wallace et al., 1993). Wallace's model is modified to account for the dermal absorption during bathing. The mass balance in the blood compartment is represented by the ordinary differential equation (ODE)

where Cblood is the DBP concentration in the blood compartment, Qalv is the inhalation rate, Calv and Cair are the DBP alveolar air concentration, and shower air concentration, respectively, ke is the elimination rate of the DBP in the blood compartment, Vblood is the volume of the blood compartment, A is the exposed body surface area, and Jx=h is the mass flux into the blood compartment. Cair is considered to be zero in this study. Based on the assumption that an equilibrium between alveolar air and blood is reached instantaneously (Wallace et al., 1993), the blood concentration can be related to the alveolar air concentration asCblood=Pblood / airCalv. Therefore, the mass balance equation of the blood compartment can be rewritten as

Assuming the mass flux through the skin is Jx=hss during the entire dermal exposure from a bath (zero-order absorption), the solution to Eq. (5) is given by

where f is a constant relating the steady-state breath concentration to the water concentration and  is the residence time of the chemical in the blood. The maximum breath concentration is estimated to be f  Cw.

DBP Concentrations in Bath Water
The DBP water concentrations were monitored during each bath. Since the bath water was well mixed before each experiment, little spatial variation in the DBP concentrations of the bath water would be expected. Despite the possible loss due to vaporization and the dermal absorption of the DBPs by the subject, no statistical differences (=0.05) in the DBP concentrations among the water samples collected at 0, 10, 20, and 30 min during each exposure at different locations within the bath were observed (Figure 1). Therefore, the DBP concentrations of the bath water may be considered constant during the entire period of each experiment. The variability in the DBP water concentrations among different experiments was also small (<15%, Table 2).
Figure 1.

Concentrations of chloroform, DCP, and TCP in bath water as a function of time (for subject A).
Full figure and legend (11K)

Table 2 - One-compartment model fit assuming zero-order dermal absorption.

Breath Concentrations of DBPs

Preexposure breath samples were collected to establish the DBP baseline levels in the expired air of each subject and to evaluate the within-subject variability in the baseline DBP levels. TCP was not detected in the breath samples of the subjects before exposure, whereas DCP was detected in the breath of subjects A and E before exposure at concentrations of 0.10 (2.7%) and 0.24 (14.5%) g / m3, respectively. The chloroform concentration in breath prior to exposure was determined to be 1.63 (14.7%) g / m3 with a range from 1–2 g / m3 for all subjects. The low chloroform concentrations and nondetectable TCP observed in expired air before exposures for all the subjects indicated that no unexpected exposures to high levels of the DBPs occurred before the experiments. The relative standard deviation of the pre-exposure chloroform concentration in expired air for each subject was less than 17%, indicating relatively small within-subject variation in chloroform background concentrations in expired air. Therefore, we assume the DBP background concentrations in breath were constant during each dermal exposure session. The DBP concentrations in breath for each subject during and following the dermal exposure were corrected by subtracting the DBP background before exposure for that subject. The maximum breath concentrations of chloroform for all the subjects during dermal exposure varied from 16 to 34 g / m3, while the maximum breath concentrations of DCP were 0.1–0.9 g / m3 (Table 2). No TCP could be detected in subject F. The maximum TCP breath concentration during exposure ranged from 0.07 to 0.25 g / m3 among the other subjects.

The time profiles of the breath concentrations for chloroform during and following exposure are plotted in Figure 2. As has been reported previously for chloroform, the breath concentrations increased during dermal exposure and tended to reach a maximum level (Jo et al., 1990; Aggazzotti et al., 1993;Weisel and Shepard, 1994; Gordon et al., 1998). The chloroform concentrations in breath began to decrease, once dermal absorption ceased and decreased rapidly between 5 and 10–15 min after exposure. The decrease of the chloroform concentrations in breath slowed down approximately 20 min after the end of the exposure. Figures 3 and 4 show the time / concentration profiles for DCP and TCP in breath, respectively, which have not been previously studied, during and after dermal exposure from bathing. The concentration levels of the HKs in breath were approximately a hundred times lower than those of chloroform during the exposures. The low concentrations of the haloketones in breath during bathing are consistent with their lower in vitro skin permeability and higher blood / air partition coefficients compared to chloroform (Xu et al., 2002; Xu and Weisel, 2003). The concentrations of the HKs in breath increased during a bath. The breath concentrations of DCP and TCP decreased quickly to a level near detection limit (0.02 g / m3) 10–15 min after exposure in most cases. Thus, it is difficult to utilize postexposure HK breath concentrations as biomarkers for dermal exposure to these compounds. The concentrations of DCP and TCP in breath during the postexposure period had a relatively large variability since the concentrations were close to the method detection limit. Measurement uncertainty may explain the unexpected increases in TCP concentrations during the postexposure period (Figure 4).

Figure 2.

Time profiles of expired chloroform concentrations in breath for six human subjects during and following 30-min dermal exposure to 37–45 g / l of chloroform in bath water at 38°C.
Full figure and legend (16K)

Figure 3.

Time profiles of expired DCP concentrations in breath for six human subjects during and following 30-min dermal exposure to 24–26 g / l of DCP in bath water at 38°C.
Full figure and legend (14K)

Figure 4.

Time profiles of expired TCP concentrations in breath for six human subjects during and following 30-min dermal exposure to 23–26 g / l of TCP in bath water at 38°C.
Full figure and legend (12K)

One-compartment Model Parameters
The values of f and  were calculated for each individual subject (Table 2) based on the uptake phase breath concentration data and the nonlinear model (Eq. (6)). The nonconvergence of the TCP data for two subjects may be caused by increased measurement uncertainty at the low TCP concentrations in breath (Table 2). This uncertainty can be reduced by improving the method sensitivity in future research. The estimate of f, the ratio of the steady-state DBP concentration in breath to the DBP concentration in bathwater, is 7.23  10- 4 for chloroform, which is comparable to the estimate obtained by Gordon et al., (1998) (5.4  10- 4). The f estimates for DCP and TCP are 1.44  10- 5 and 1.07 10- 5, respectively. Therefore, on average, the maximum concentrations in exhaled breath for chloroform, DCP, and TCP during a 30-min bath are expected to be 0.72, 1.44  10- 2, and 1.07  10- 2 g / m3, respectively, for the subjects if the DBP concentration is 1 g / l in bathwater.

The estimated uptake-phase residence times () for chloroform, DCP, and TCP ranged from 5.87 to 32.2, 3.75 to 16.7, and 8.72 to 53.2 min, respectively. Our previous inhalation study showed that the residence times of DCP and TCP were approximately 4.5 and 6.6 min, respectively (Xu and Weisel, 2004). Longer residence times were calculated following dermal exposure than from the inhalation study because of the gradual dermal dose delivery during exposure. Based on a 30-min bath study, Gordon et al., (1998) estimated that the residence time for chloroform was 8.23.1 min (n=10).

Estimating in vivo Skin Permeability

The permeability coefficients (Kp) of the DBPs can be estimated by an equation derived from Eqs. (7) and (8)as follows:

For dermal exposure including a nonsteady-state period, the calculated Kp is defined as an effective Kp (Kpeff) (McKone and Howd, 1992; McKone, 1993). However, the estimated Kpeff may be a good approximation of the steady-stateKp when the lag time of a chemical across the skin is much less than the dermal exposure duration (tlagtexp, e.g. texp). A lag time in stratum corneum was estimated, ranging from 10 to 30 min for chloroform (U.S. EPA, 1985; McKone, 1993; Xu et al., 2002). Lag times of HKs were estimated to be 1–2 min (Xu et al., 2002). Thus, during the 30-min dermal exposures of this study, the steady-state conditions required for calculating the steady-state in vivo Kp estimates were probably attained for the HKs but not for chloroform. The Kpeff estimates for DCP and TCP were determined to be 7.53  10- 4 and 4.54  10- 4 cm / h, respectively. The estimated average Kpeff of chloroform was 0.015 cm / h. Thus, chloroform was approximately 20–30 times more permeable than HKs. The in vivo effective skin permeability of chloroform for humans was reported to range from 0.01 to 0.42 cm / h based on physiologically based pharmacokinetic models (PBPK) and breath measurement data obtained from shower or bath studies (Jo et al., 1990;McKone, 1993; Gordon et al., 1998; Corley et al., 2000). Our estimate for chloroform is comparable to the lower bound of this reported range. This simple estimation approach may be useful for calculating an approximate Kpeff based on the indirect breath measurement of dermal absorption when there is not enough information to develop complete PBPK models for compounds like HKs.

The uncertainties in the model parameters such as  may lead to uncertainty in the Kpeff estimates. Wide ranges of  for chloroform (1 - >10 min) have been reported (Raymer et al., 1991; Weisel et al., 1992; Pleil and Lindstrom, 1997;Wallace et al., 1997). Future large-scale studies may help reduce the range present in these parameters if they are due to analytical uncertainty, or they may represent real difference among individuals associated with phenotype or genotype differences causing variation in metabolism of chloroform or variable physiological parameters of the subjects altering chloroform distribution within the body.

DBP Mass Exhaled

The amounts of chloroform, DCP, and TCP exhaled during the entire experiment, including the exposure and postexposure periods, for each individual subject was calculated based on the area under the background-corrected breath concentration curves (Table 3). Individual alveolar inhalation rates under sedentary conditions estimated using Radford nomogram (Table 1) were used for the calculations since all the subjects were at rest during and after the bath. The exhaled amount was normalized with the respective DBP concentration of the bath water and expressed in units of g DBP per g / l DBP in water. The values of total exhaled amount for chloroform ranged from 0.06 to 0.14 g per g / l. An average value of 0.1 g per g / l was reported by Gordon et al., (1998) in a 30-min bath study. The total exhaled amounts of DCP and TCP were 1.3  10- 3and 0.5  10- 3 g per g / l, respectively, during the entire experiment period. The total amounts of HKs expired were approximately 2–3 orders of magnitude lower than that of chloroform, consistent with their lower permeability and higher blood / air partition than chloroform. The normalized exhaled amounts of the DBPs during the postexposure period were also calculated (Table 3). After the dermal exposure, the amount of chloroform expired was in a range from 0.02 to 0.09 g per g / l in water, which was also more than 100-fold the exhaled HK amounts that resulted from the 30-min dermal exposure during the postexposure period.

Table 3 - Exhaled amount of DBPs during and following dermal exposure.

This study has shown that HKs penetrate human skin and can be measured in expired breath air during bathing. However, HKs were generally only measurable within 10–15 min after the dermal exposure ended due to their low postexposure breath concentration and short residence times in the human body. Based on a one-compartment pharmacokinetic model, the permeabilities of HKs were found to be 0.01–0.1 times that of chloroform under the experimental conditions used. This study provides the data for evaluating dermal absorption of HKs and related health risks of these disinfection by-products during bathing. Future research with a larger sample size (human subjects) is needed to extrapolate these results to the general population.

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