Welcome to Scribd. Sign in or start your free trial to enjoy unlimited e-books, audiobooks & documents.Find out more
Download
Standard view
Full view
of .
Look up keyword
Like this
4Activity
0 of .
Results for:
No results containing your search query
P. 1
Computational Toxicology of Chloroform: Reverse Dosimetry

Computational Toxicology of Chloroform: Reverse Dosimetry

Ratings: (0)|Views: 202|Likes:
We demonstrate the use of a computational framework that integrates physiologically
based pharmacokinetic (PBPK) modeling, Bayesian inference, and Markov chain Monte Carlo simulation
to obtain a population estimate of environmental chloroform source concentrations consistent
with human biomonitoring data. The biomonitoring data consist of chloroform blood
concentrations measured as part of the Third National Health and Nutrition Examination Survey
(NHANES III), and for which no corresponding exposure data were collected.
We demonstrate the use of a computational framework that integrates physiologically
based pharmacokinetic (PBPK) modeling, Bayesian inference, and Markov chain Monte Carlo simulation
to obtain a population estimate of environmental chloroform source concentrations consistent
with human biomonitoring data. The biomonitoring data consist of chloroform blood
concentrations measured as part of the Third National Health and Nutrition Examination Survey
(NHANES III), and for which no corresponding exposure data were collected.

More info:

Published by: Environmental Health Perspectives on Sep 29, 2008
Copyright:Public Domain

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF, TXT or read online from Scribd
See more
See less

02/01/2013

pdf

text

original

 
1040
VOLUME
116
|
NUMBER
8
|
August 2008
Environmental Health Perspectives
Research
To understand the effects on public health of exposure to environmental chemicals requiresestablishing relationships among events alongan exposure–health evaluation–risk assessmentcontinuum (National Research Council 2006).Biomonitoring data, such as chemical concen-trations in tissues and fluids, are a measure of internal exposure and represent one event alongthe continuum to be linked with external expo-sure and biologically effective dose. We focushere on the relationship between internal andexternal exposure, with external exposure beinga measure of environmental chemical concen-tration in contact with the body. Often, how-ever, biomonitoring data are reported withoutcorresponding external exposure data, leavingthe relationship between internal and externalexposure as one to be determined; establishingthis relationship involves the reconstruction of past external exposure or dose, from biomoni-toring data collected at some later time. Suchexposure reconstruction can be addressed atboth the individual and the population level. A procedure for determining an estimate of external exposure consistent with biomonitor-ing data measured in a population has beentermed “exposure reconstruction” or “reversedosimetry.” A population-based estimate of exposureshould account for the intrinsic heterogeneity (variability) in the population, both in themodeling of the disposition of the chemicalin the body, and in the description of theexposure conditions. Additionally, the bio-monitoring information itself, considered as a whole, should reflect the variability in thepopulation from which it arises.Tan etal. (2006) incorporated variability into the reverse dosimetry of chloroform usinga combined physiologically based pharmaco-kinetic (PBPK) and shower exposure model, with external exposure calculated using anexposure conversion factor (ECF) distribu-tion. The ECF distribution was obtained by inverting the output of a Monte Carlo (MC)simulation for chloroform concentration inblood using, as input, a preselected referencevalue for chloroform concentration in tap water. The product of the ECF distribution with an observed blood concentration pro-vides a distribution of tap water concentra-tions corresponding to that blood level. Although the ECF distribution provides apopulation estimate of exposure, its accuracy is limited to the case in which tissue dose islinearly related to external exposure. In thisarticle, we reconsider the work of Tan etal.(2006) with an approach to reverse dosimetry using Bayesian inference in place of the ECFdistribution.In addition to the work of Tan etal.(2006), exposure reconstruction for chloroformusing PBPK modeling has appeared inGeorgopoulos etal. (1994) and Roy etal.(1996) in the form of a maximum likelihoodcalculation. In this case, the biological modelparameters remained as fixed values represent-ing an average or reference individual and didnot account for population variability. Thereport by Tan etal. (2007) included a calcula-tion of chloroform tap water concentrationusing Bayes’ theorem, but with the prior distri-bution taken as unity, which reduced Bayes’theorem to a maximum likelihood calculation.Previous work using Bayesian methodsfor exposure reconstruction for other chemi-cals has appeared in Miller etal. (2002), Sohnetal. (2004), and Allen etal. (2007). The work of Miller etal. (2002) described a gen-eral procedure for individual dose reconstruc-tion using Bayesian inference and Markov chain Monte Carlo (MCMC) simulation. Inthis case, the model for chemical disposition was a traditional compartment-based kineticmodel for plutonium-239, which was appliedto individual exposure reconstruction for
239
Pu from urine measurements. Althoughthe model used was not a PBPK model anddid not address population-based measure-ments and variability, it served as the moti-vating example in formulating the details of the method we present in this article.Sohn etal. (2004) used a PBPK model andBayesian inference to reconstruct exposure totrichloroethylene from detailed concentration–time data for eight individuals. They obtained apopulation estimate by treating the individualsas a random sample from a larger population without the use of a hierarchical populationmodel or the use of MCMC simulation. They 
 Address correspondence to B. Reisfeld, 1370 CampusDelivery, Colorado State University, Fort Collins, CO80523 USA. Telephone: (970) 491-1019. Fax: (970)491-7369. E-mail: brad.reisfeld@colostate.edu We thank F. Bois, D. Marino, and T. Covingtonfor their advice and assistance with MCSim andMarkov chain Monte Carlo modeling.This study was supported by the National Instituteof Environmental Health Sciences through grantsK25 ES11146 and K25 ES012909 and the U.S.Environmental Protection Agency through STAR Research Assistance Agreement R833451.The authors declare they have no competingfinancial interests.Received 16 November 2007; accepted 24 April2008.
Computational Toxicology of Chloroform: Reverse DosimetryUsing Bayesian Inference, Markov Chain Monte Carlo Simulation,andHuman Biomonitoring Data
Michael A. Lyons,
1,2,3 
Raymond S.H. Yang,
1,2 
Arthur N. Mayeno,
1,2 
and Brad Reisfeld 
1,2,3 
1
Quantitative and Computational Toxicology Group,
2
Department of Environmental and Radiological Health Sciences, and
3
Departmentof Chemical and Biological Engineering, Colorado State University, Fort Collins, Colorado, USA
B
 ACKGROUND
:
One problem of interpreting population-based biomonitoring data is thereconstruction of corresponding external exposure in cases where no such data are available.
O
BJECTIVES
:
 We demonstrate the use of a computational framework that integrates physiologically based pharmacokinetic (PBPK) modeling, Bayesian inference, and Markov chain Monte Carlo sim-ulation to obtain a population estimate of environmental chloroform source concentrations consis-tent with human biomonitoring data. The biomonitoring data consist of chloroform bloodconcentrations measured as part of the Third National Health and Nutrition Examination Survey (NHANES III), and for which no corresponding exposure data were collected.
M
ETHODS
:
 We used a combined PBPK and shower exposure model to consider several routes andsources of exposure: ingestion of tap water, inhalation of ambient household air, and inhalation anddermal absorption while showering. We determined posterior distributions for chloroform concen-tration in tap water and ambient household air using U.S. Environmental Protection Agency TotalExposure Assessment Methodology (TEAM) data as prior distributions for the Bayesian analysis.
ESULTS
:
Posterior distributions for exposure indicate that 95% of the population represented by the NHANES III data had likely chloroform exposures
67µg/L in tap water and
0.02µg/L inambient household air.
C
ONCLUSIONS
:
Our results demonstrate the application of computer simulation to aid in the inter-pretation of human biomonitoring data in the context of the exposure–health evaluation–risassessment continuum. These results should be considered as a demonstration of the method andcan be improved with the addition of more detailed data.
EYWORDS
:
Bayesian, biomonitoring, chloroform, Markov chain Monte Carlo, MC, MCMC,Monte Carlo, PBPK, reverse dosimetry.
Environ Health Perspect 
116:1040–1046 (2008).doi:10.1289/ehp.11079 available via 
http://dx.doi.org/ 
[Online 26April 2008]
 
evaluated Bayes’ theorem directly by using MCsimulation to build up a library of terms forthe likelihood and prior incorporating distribu-tions for PBPK model parameters to accountfor population variability. Allen etal. (2007) recently reconstructedexposure to methylmercury (MeHg) in women of childbearing age and pregnant women, using a method similar to that pre-sented here. Their application involved twostages of Bayesian updating to recalibrate thePBPK model parameters along with oralabsorption of MeHg for the subpopulation of interest. Both the method of Allen etal.(2007) and the method presented here arebased on the work of Gelman etal. (1996), which was presented as a general method of parameter estimation in PBPK models. Thismethod originally was applied to PBPK modelcalibration, and examples and reviews can befound in a number of articles (Bernillon andBois, 2000; Covington etal. 2007; Hack etal.2006; Jonsson 2001). We view reverse dosimetry as a type of PBPK model calibration problem, whichallows us to use established methods and toolsto aid in the interpretation of population-based biomonitoring data.
Reverse dosimetry.
The fundamental prob-lem underlying reverse dosimetry is to relate ameasured internal dose, or tissue concentra-tion,
, to an unmeasured external exposureor dose,
, given a deterministic model
 f  
(weconsider
 f  
to be minimally a PBPK model).The usual mode of operation for
 f  
is to solvethe “forward problem” of determining the tis-sue concentration given a known external dose:
=
 f  
(
). If our model is such that anappropriate inverse
 f  
–1
can be found, then thereverse problem can be solved as
=
 f  
–1
(
).Typically, however,
 f  
is such that an inverseeither does not exist or may not be unique, ormay be unstable, meaning that a small changein the data may lead to a large change in out-put of the inverse function; that is, the reverseproblem is usually “ill-posed” (Hadamard1902). Additional complications arise whenconsidering the population-based nature of thebiomonitoring data where population variabil-ity becomes a significant factor that needs to beincorporated into the solution for
. Also,biomonitoring data represent accumulation of chemicals in the body from all possible sourcesand routes of exposure, and we may need toaccount for multiple simultaneous indepen-dent inputs into the model.
Bayesian inference.
 A Bayesian approachdetermines
as a probability distributionrather than a single value, the starting pointbeing the treatment of all observables and para-meters of interest as random variables. Theexternal dose
is assigned a “prior” probabil-ity distribution representing knowledge about
before consideration of the data
. Theprior distribution is updated via Bayes’ theo-rem, into a “posterior” probability distributionfor
conditioned on the data
. Bayes’ the-orem can be written as where
 p 
(
) is the prior,
 p 
(
|
) is thelikelihood, and
 p 
(
|
) is the posterior.The likelihood is the conditional distribution
 p 
(
|
) viewed as a function of 
and whose functional form is based on the specifi-cation of a measurement model that describesthe difference between observation and modelprediction in terms of an error. A significant aspect of PBPK models is thatall of the parameters have a physical or biologi-cal interpretation: they are not arbitrary. Wecan use knowledge regarding possible ranges,central values, and measures of dispersion, as well as specific data from separate studies, todefine informative prior distributions.The product of the prior and likelihoodgives (up to a normalization constant) the pos-terior distribution containing all informationregarding the parameter
consistent withthe data and prior information. The posteriordistribution is the solution of the reverse prob-lem, and all further inferences regarding
ismade from it in terms of expectation values of functions of 
.For most cases of practical interest, the nor-malized posterior distribution is evaluated vianumerical simulation. MCMC simulation isthe standard method used for Bayesian analysis(Gelman and Rubin 1996; Gilks etal. 1996).MCMC simulation refers to a class of iterativesimulations in which the random variables of interest are drawn from a sequence, or chain, of distributions that eventually converge to a sta-ble posterior distribution. These chains can bedetermined by rejection sampling algorithms where a random draw is accepted or rejectedbased on a simple probabilistic rule (e.g., theMetropolis-Hastings algorithm; see Gilks etal.1996). Convergence can be assessed by runningmultiple chains and comparing the variance within and between the sequences via a “poten-tial scale reduction” factor R 
^
(Gelman etal.2004). R 
^
is such that lim
→∞
^
= 1, where
isthe number of iterations. Gelman etal. (2004)recommend continuing iterations until R 
^
<1.1for each parameter of interest. Once conver-gence is obtained, the multiple chains can beaggregated and considered to be a sample froma discrete approximation to the posterior distri-bution. The expectation value
[
(
)] of anarbitrary function
(
) can be estimated by drawing {
Dk,
k =
1, . . . ,
} from the poste-rior and calculating the following:For example, we can estimate the expectedvalue for
as the sample mean of the poste-rior distribution. Note also that
can consistof multiple components, the posterior being a joint distribution from which we can calculatemarginal distributions for each component.The above discussion describes the basicelements of a Bayesian analysis that wouldapply to an estimate of external dose for anindividual based on data collected for that indi-vidual. The reverse dosimetry problem, how-ever, is a problem of statistical inference: we wish to determine an estimate of exposure forthe general population based on biomonitoringdata collected from a representative sample of that population. We can address this statisticalaspect of the problem by combining Bayesiananalysis with a population model.
Materials and Methods
 We applied the Bayesian population analysis of Gelman etal. (1996) to the problem of reversedosimetry for chloroform to obtain populationestimates of chloroform concentrations in tap water and ambient household air under resi-dential exposure conditions. We viewed reversedosimetry as a type of model calibration prob-lem where, using an otherwise calibratedmodel, we determined unmeasured exposureparameters based on the measured biomonitor-ing data. The basic elements of the analysisinclude a PBPK + shower model, prior chloro-form concentration measurements in tap waterand ambient air from the U.S. EnvironmentalProtection Agency (EPA) Total Exposure Assessment Methodology (TEAM) study (Wallace 1997), and biomonitoring data in theform of chloroform concentrations in bloodmeasured as part of the Third National Healthand Nutrition Examination Survey (NHANESIII) (Centers for Disease Control andPrevention 1996). With some noted excep-tions, we use the PBPK + shower model, para-meter distributions, definition of exposure, andexperimental data provided in Tan etal.(2006, 2007); however, these elements have adifferent rationale and purpose in the contextof the Bayesian population framework pre-sented here, than that of the ECF distributionor likelihood-based methods.The TEAM study data we used here werecollected during 1981–1984 from a differentpopulation than that used for the NHANES IIIdata, which were gathered during 1988–1992.No exposure data were collected correspondingto the NHANES III biomonitoring data, andthe objective here is to determine an estimatefor such corresponding exposure.The reverse dosimetry problem for chlo-roform is to relate a sample of chloroformblood concentrations,
, to an unmeasuredpopulation distribution of environmentalchloroform source concentrations,
, giventhe deterministic model
 f  
:
. The
E h h
D Dk 
(
)
[ ]
(
)
=
1
1
.
 p C C p C C p
D T T D
|
(
)
|
(
)
(
)
,
Computational toxicology of chloroform
Environmental Health Perspectives
VOLUME
116
|
NUMBER
8
|
August 2008
1041
 
deterministic model
 f  
=
 f  
(
,
φ
,
) is thePBPK + shower model and represents thesolution to a set of differential equationsderived from biological and physical principlesconsidered to be common to all members of the population; it is a function of time
and aset of parameters whose values distinguish thevarious individuals. We divided the parame-ters into those that are to be updated in theanalysis, that is, the unmeasured source con-centrations
= (
,
 A 
), and those that areto remain fixed, where
and
 A 
are the con-centrations in water and air, respectively. Wedesignate the fixed parameters by 
φ
, which canbe single-point values or fixed distributionsrepresenting pharmacokinetic, shower model,and other exposure parameters such as drink-ing water intake and shower duration.Population variability is described by con-sidering individual values for
to ariseindependently from a population distributionparameterized by a population mean µand apopulation variance
Σ
. The introduction of population parameters induces a hierarchicalstructure among the model parameters that,along with the specification of the determinis-tic model quantities and error, defines thepopulation model. The population model,specifying the conditional dependenciesamong the population and individual para-meters and the link through the deterministicmodel to the data and error, can be summa-rized as a graphical model (Figure1). Here,blood and source concentrations are related atthe individual level through the deterministicmodel, with source and error parameter val-ues for each individual arising independently from population-level distributions.The Bayesian analysis proceeds asdescribed above, but with the additionalstructure among the parameters in the popu-lation model incorporated into the terms inBayes’ theorem. Writing the joint prior prob-ability distribution as
 p 
(µ,
Σ
,
,
σ 
2
), we usethe conditional dependencies encoded in thegraphical model to obtain
 p 
(µ,
Σ
,
,
σ 
2
) =
 p 
(µ)
 p 
(
Σ
)
 p 
(
|µ,
Σ
)
 p 
(
σ 
2
). Similarly, thelikelihood is
 p 
(
|µ,
Σ
,
,
σ 
2
) =
 p 
(
|
,
σ 
2
). Bayes’ theorem then takes the formOnce we specified the prior distributionsfor µ,
Σ
, and
σ 
2
, the next step was to calculatethe posterior distribution conditioned on theobserved data and to calculate the statisticalquantities for the parameters of interest.Figure 2 illustrates the relationships amongthe basic elements used in the Bayesian analy-sis. Random draws from the prior distributionsfor water and air concentrations, and fromfixed distributions for pharmacokinetic, showermodel, and other exposure parameters, defineindividual parameter sets from which we calcu-lated model predictions for chloroform bloodconcentrations. We compared predicted bloodconcentrations with the observed concentra-tions and accepted the sampled values for water and air with probability defined in theMCMC algorithm. Using the output parame-ters of one iteration as the input for the next, we repeated the procedure until the parameterdistributions for water and air became stable,and then transformed the prior distribution tothe posterior distribution.The analysis of the reverse dosimetry problem consists of the following steps:Specification of the probability model: speci-fication of the joint probability distributionincorporating the PBPK + shower model,hierarchical population model, measurementmodel, and the specification of prior parame-ter distributionsBayesian inference: calculation of the poste-rior distribution conditioned on the observed
 p C  p C C p
S V  V S
μ σ μ σ μ σ , , , |
(
)
| , , ,
(
)
, , ,
(
)
ΣΣ Σ
222
| ,
(
)
| ,
(
)
(
)
(
)
(
)
 p C C p C p p
V S
σ μ μ σ 
22
Σ Σ
.
Lyons et al.
1042
VOLUME
116
|
NUMBER
8
|
August 2008
Environmental Health Perspectives
Figure 3.
Schematic of PBPK + shower model for chloroform (Tan etal. 2006).
ShowerAmbient airExhalationInhalation
    A   r   t   e   r    i   a    l    b    l   o   o    d    f    l   o   w    V   e   n   o   u   s    b    l   o   o    d    f    l   o   w
DermalIngestionAlveolar airLung bloodRapidlyperfusedSlowlyperfusedSkinFatLiverKidneyMetabolismMetabolism
Figure 1.
Graphic model (adapted from Bernillon andBois 2000). Circles represent unknown quantities tobe updated via Bayes’ theorem: population mean (µ)and variance (
Σ
), concentrations (
), and error (
σ 
2
).Squares represent the known quantities of time (
),PBPK model and exposure parameters (
φ
), and mea-sured blood concentrations (
). The triangle repre-sents the deterministic model (
). The solid arrowsrepresent conditional dependence, and the dashedarrow represents a deterministic link. Individualsare represented by the layered boxes, and are con-sidered to be a subset of the population.
Population
μΣ
Individual
φ
σ 
2
Figure 2.
Basic elements for reverse dosimetry ofchloroform using Bayesian analysis.
Fixeddistributionsfor PBPK/shower modeland exposure
Prior distributions(TEAM data)PBPK + showermodelPredicted bloodconcentrationsMCMCalgorithmObserved bloodconcentrations(NHANES III data)
PriorPosterior

Activity (4)

You've already reviewed this. Edit your review.
1 hundred reads
1 thousand reads
samfargh liked this
bhalo_0907 liked this

You're Reading a Free Preview

Download
scribd
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->