Volume II Chapter 6.0 Pages 1 of 2 page next page 2
  • 6. PHARMACOKINETICS 6-1
    • 6.1. INTRODUCTION 6-1
    • 6.2. DAILY BACKGROUND LEVELS 6-2
      • 6.2.1. Basis for Calculation 6-2
      • 6.2.2. Daily Intakes 6-7
    • 6.3. COMPARTMENTAL MODELING 6-14
6. PHARMACOKINETICS

6.1. INTRODUCTION

The pharmacokinetic profiles of CDDs and the CDFs are quite complex. A thorough analysis and understanding of these pharmacokinetic data would be very helpful in ensuring that exposure assessments for these compounds are reliable. In addition, such information would be useful in providing enhanced knowledge and understanding for the purposes of risk assessment. Previous drafts of this chapter included a discussion on bioavailability of CDD/Fs. Since this topic is only loosely related to pharmacokinetics, it was decided to move this discussion to an appendix and it now appears in Appendix C of this Volume.

Exposure to 2,3,7,8-TCDD and related compounds results in numerous species and tissue specific toxic and biological responses. Many, if not, all of these responses are mediated by a soluble intracellular protein, the aryl hydrocarbon (Ah) receptor, to which 2,3,7,8-TCDD binds with high affinity. After 2,3,7,8-TCDD and related compounds bind to this Ah receptor the complex undergoes a transformation process involving dissociation of hsp90. The transformed receptor complex is then able to bind with high affinity to a specific DNA sequence referred to as a dioxin responsive enhancer (DRE). The conserved nature of the DRE and Ah receptor is also indicated by the ability of transformed 2,3,7,8-TCDD: Ah receptor complexes from a wide variety of species to bind to the DRE. Studies also indicate a similarity in DNA recognition by Ah receptor from a variety of species suggestive of a functional role of this sequence in 2,3,7,8-TCDD responsiveness (Denison et al., 1991; Gasiewicz and Henry, 1991; Perdew and Hollenbeck, 1990; Andersen and Greenlee, 1991). Thus the definition of "disposition" may have to be extended to include suborgan or subcellular sites in order to more fully describe the congener, species, and train specific pharmacokinetics (dosimetry) of these compounds.

Pharmacokinetic analysis may be used in several ways to aid in the exposure and dose assessment of foreign chemicals. They may, for example, allow for predicting the time and profile of elimination of chemicals from the body. The redistribution of CDDs among the various tissues and organs, which may occur during elimination, can be accounted for and tracked. Effects on disposition which may result from altered physiology, such as sudden weight loss or from lactation, can be incorporated and thus adequately considered in exposure and risk assessments. Lactation is known to be an efficient route for the transfer of many of these chemicals from mother to offspring (Nau et al., 1986; Bowman et al., 1989).

Pharmacokinetic analyses can be used to estimate background exposure levels from body burden data. They can also be used to estimate uptake rates from various food sources, elimination rates and times from the body, and to estimate tissues levels from blood and adipose tissue monitoring. In addition, with the appropriate data on several congeners, estimates can be made for other congeners about which less data are available.

The remainder of this chapter will cover areas of pharmacokinetics pertinent to exposure assessment. Background levels and daily uptake of 2,3,7,8-TCDD will be reviewed and discussed; a method for the calculation of uptake of other congeners from food will be outlined; use of a compartmental model to estimate daily uptake will be demonstrated; a method will be outlined and reviewed for determining internal tissue concentrations from monitored blood and/or adipose tissue; exposure through lactation will also be discussed.

6.2. DAILY BACKGROUND LEVELS

6.2.1. Basis for Calculation

Physiologically based pharmacokinetic (PBPK) models are convenient and useful methods for describing and predicting disposition of foreign chemicals in the body. These models take into account physiologic and biochemical processes such as blood flows, metabolism, and renal clearance, and describe the body according to its normal anatomy. PBPK models can, given adequate data, predict disposition from one exposure scenario to another and even from species to species. One such model was developed for 2,3,7,8-TCDF (King et al., 1983) and is used here with some modifications.

The anatomic regions depicted in the King model are the blood, liver, fat, skin, and muscle. The remaining organs of the body are lumped together as the "carcass." Input may be by a variety of routes, but for the purposes of this discussion is considered to occur through the gastrointestinal system by continuous chronic dosing. This is consistent with the findings of Chapters 4 and 5 that most of these compounds enter the body through the gastrointestinal tract as a result of the consumption of products containing animal fat. The pertinent equations follow.

For the liver:

Formula V3 6-1

The clearance in the liver is considered to be by metabolic processes. For the fat:

Formula V3 6-2

Where all terms are analogous as those in Equation 6-1.
Note that there is no metabolic elimination assumed. The only disappearance of material from the fat is assumed to be diffusion driven and is accounted for in the above mass balance equation. Equations for the skin, carcass, and muscle are analogous to that for fat. The equation for the blood is:

Formula V3 6-3

Some assumptions may be made to simplify the model for use to estimate daily background doses. If steady state is assumed, then the equations for the individual organs can be summed. The resultant equation for the liver is then:

Formula V3 6-4

and at steady state

Formula V3 6-5

and

formula 6-6

and hence

Formula V3 6-7

When clearance is expressed in days, D is the daily intake. Clearance can be approximated from the half-life information according to the following equations:

Formula V3 6-8
and
Formula V3 6-9

The volume of distribution may be estimated as in King et al., (1983) according to:

Formula V3 6-10

With substitution equation (6-7) becomes:

Formula V3 6-11

It is important to note that two major assumptions are in effect when the above formula is used to calculate average daily uptake. First steady state conditions are assumed. Given that the half-life of some of these compounds (e.g., 2,3,7,8-TCDD) are at least 5 years, it would take well over 15 years to reach 90 percent of steady state, and over 30 years to reach 99 percent of steady state levels.

Thus, the assumption of steady state is only reasonable if background environmental concentrations are relatively similar and constant throughout the nation. Under such conditions even the normal movement from one geographical location to another would result in relatively constant exposures. Also implicit in this assumption is that bioavailability is relatively constant through the nation.

Given that the source of this background exposure is believed primarily due to consumption of foods containing animal fat (see Chapters 4 and 5), the assumption of steady state for adults might be considered a reasonable assumption. Exceptions are those individuals who may for a portion of their adult lives be consuming foods with unusually high levels of these compounds.

It would be expected, however, that those individuals would have higher than average body burdens, and hence would not be considered to have only average background exposure, but would rather be considered part of a source-specific exposure group. Conditions such as sudden weight loss and lactation would also alter the steady state condition.

However, for purposes of calculating daily background exposure levels the sampling of tissues for body burden must be so designed to account for such deviations in the average. In summary, for adults (over 25 years of age) not in a source-specific exposure group, the steady state assumption is a reasonable approximation. It should be remembered, however, that the longer the biological half-life the longer it would take to reach steady state. A compound with a half life of 10 years, for example, would take over 50 years to reach 90 percent of the steady state value.

The second major assumption is that these compounds are eliminated from the body by monophasic kinetics. Biphasic elimination is very possible for many of these compounds. Data gathered to calculate elimination rates or half-lives would only reveal biphasic elimination profiles if gathered several years after the last exposure. Using only the short term half-life would result in an underestimated value for half-life and an overestimate of daily intake.

This is particularly problematic for those compounds with extremely long half-lives and for which few data exist. In Section 6.2.2., an approach to calculating half-lives for some of these compounds will be presented. Also, the elimination kinetics are assumed to be constant over the entire life of the individual. Sudden weight loss and lactation would, for example, be conditions which violate that assumption. Again, it would be assumed that for calculation of daily intake due to background exposure the body burden data from such individuals would be identified and calculations handled accordingly.

6.2.2. Daily Intakes
table Figure 6-1 Sample Calculation of Daily Intake for 2,3,7,8-TCDD.
Figure 6-1 shows a sample calculation for 2,3,7,8-TCDD using the above procedure. A fat volume of 14 L was chosen, representing 20 percent of the body weight. Also, for the purposes of this example, 1 ml of tissue was assumed to be equivalent to 1 gm.

Table 6-1 shows the estimated daily intake of 2,3,7,8-TCDD at several conditions. The range of daily intakes calculated are in agreement with those reported elsewhere (Fürst et al., 1991; U.S. EPA, 1994).

In order to perform similar calculations for other congeners three pieces of information are necessary. First, concentrations in the adipose tissues must be known.
expand table Figure V3 6 -1

Second, the half-lives of the compounds within the body must be known. Third, some understanding of the kinetics and exposure conditions to assure that steady state conditions were achieved at the time of monitoring.

Concentrations of various congeners in adipose tissues can be found in several sources (Stanley et al., 1986; Schecter, 1991). Values range from around 2 ppt for 2,3,7,8-TCDF to several hundred ppt for 1,2,3,4,6,7,8,9-OCDD.

Half-lives could be determined from elimination data, if available. Methods have been suggested to determine the half-lives of such compounds from uptake data relative to 2,3,7,8-TCDD. Schlatter (1991) has proposed one such method. The following has been adapted from that proposed method. Manipulation of Equation 6-11 results in:

Formula V3 6-12

For some other congener x:

Formula V3 6-13

Where symbols are same as for equation (6-12) and subscript x applies to compound x.

table Table 6-1 Calculated Daily Intakes for 2,3,7,8-TCDD.  
expand table Table V3 6 -1

Thus the ratio of concentrations of TCDD to x can be described by:

Formula V3 6-14

With algebraic manipulation and simplification Equation 6-14 becomes:

Formula V3 6-15

Assuming intake, D, to be mostly from the food, especially animal fat products, D can be related to absorption from these foods according to:

Formula V3 6-16
and
Formula V3 6-17

As a result the half-life for compound x can be described by:

Formula V3 6-18

When the absorption rate constants for each congener are equal or when the difference between them is small compared to differences in other parameters (concentration, half-lives), Equation 6-18 can be further simplified to:

Formula V3 6-19

Before using the above approach to calculate half-lives for some of the other substances of interest it is well to briefly highlight one of the assumptions in this approach. The relationship of half-life to elimination as described in Equation 6-9 only applies to simple single compartment kinetics. These compounds would not necessarily be expected to behave in such a manner. However, the error introduced by such an assumption is not great if the one phase predominates over the other, or if it is remembered that the calculation applies to one phase only. In fact, as will be discussed in a subsequent section, it is believed that for these chemicals the relationship between half-life and elimination as described here is a reasonable approximation.

It should be noted that for some of these substances exposure is expected from other than food sources. For such cases Equation 6-18 would be modified to include these other sources as follows:

Formula V3 6-20

Again, if the differences between the absorption rate constants for TCDD and x are judged to be small, then the variation of Equation 6-19 can be used, presented as Equation 6-21, Table 6-2 shows the results of some half-lives calculated in this manner.

Formula V3 6-21

The half-lives calculated using Equation 6-19 for the first three compounds in Table 6-2 agree with those calculated by Schlatter (1991).

The large difference in the two calculations for OCDD is due to significant differences in absorption rates between the TCDD and the OCDD. Schlatter (1991) notes that for some compounds, including OCDD, corrections were made of differences in absorption. No explanation was offered on how this was done. In U.S. EPA (1993), results are summarized that indicate a possible several-fold greater oral absorption of TCDD over OCDD. This adjustment would result in a calculated half-life closer to that calculated by Schlatter.

In summary, this section illustrates a method for calculating the half-lives of similar behaving compounds. Several pieces of information are necessary: 1) the concentration in the body of 2,3,7,8-TCDD; 2) the half-life of 2,3,7,8-TCDD; 3) the concentration of the substance of interest in the body; 4) the concentration of the substance of interest in the media from which exposure occurs; and 5) the differential absorption rates for TCDD and the substance of interest.

From the half-life information, average daily intakes may be calculated, when steady state can be assumed, by using Equation 6-12. Caution should be exercised when calculating daily intakes for those compounds with very long half-lives such as OCDD in the above example.

table Table 6-2 Half-life Calculations.  
expand table table V3 6 - 2

6.3. COMPARTMENTAL MODELING

As previously discussed and also discussed elsewhere (U.S. EPA, 1994), PBPK models are very useful for describing and predicting the disposition of chemicals in the body. They are generally designed for predicting some measure of dose at a target site. They are also used to extrapolate from one species to another, between different doses, and between different routes of exposure.

Several PBPK models have been published specifically for 2,3,7,8-TCDD (Leung et al., 1990; Leung et al., 1988). Also, as previously discussed, a model for 2,3,7,8-TCDF (King et al., 1983) is also available and from which were derived the equations for estimating daily intake from body concentrations at steady state conditions. Most of these models have been developed to describe in great detail the metabolism and binding of TCDD within the body, for the purpose of estimating target tissue dose.