Human Biomonitoring for Environmental Chemicals (2006) / Chapter Skim
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5 Interpretation of Biomonitoring Results
5 Interpretation of Biomonitoring Results
Pages 132-200
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From page 132... ...
This chapter describes various options for interpreting biomonitoring results with respect to those two questions and discusses how the analysis and interpretation can be used in different biomonitoring settings. The settings in which biomonitoring results may need interpretation include the workplace, the doctor's office, screening of the general population, and study of specific subpopulations.
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From page 133... ...
INITIAL REVIEW OF BIOMONITORING DATA Interpreting biomonitoring results depends on the availability of various types of information, including data on exposure, toxicity, and toxicokinetics. If toxicity information is unavailable, the results cannot be put into a risk
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From page 134... ...
OVERVIEW OF INTERPRETIVE OPTIONS FOR BIOMONITORING DATA Two main options for interpreting biomonitoring results -- descriptive and risk-based approaches -- appear in Figure 5-1. This figure is organized from simplest to most complex approaches, with the potential for interpreting health risks also increasing from top to bottom.
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From page 135... ...
. Workplace biologic reference values are another descriptive option for interpreting biomonitoring results in the general population.
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From page 136... ...
. Using existing risk assessments for interpreting biomonitoring data can help to put biomonitoring results into a broad risk
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From page 137... ...
Some of the recommendations presented by the committee in Chapter 7 attempt to address the biomarker data gaps through a research agenda. When data gaps are filled, there may be disagreement about how to apply the data for interpreting biomonitoring results.
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From page 138... ...
138 B B B B B B B 5 5 5 5 5 Where Presented Chapter Chapter Appendix Appendix Appendix Chapter Chapter Appendix Appendix Chapter Appendix Appendix -pyridinol. context context dose trichloro-2 = new risk risk exposure amount amount daily TCP Options into into relationship relationship from from obtain and develop to estimate acid; animals dose dose to results results to in pharmacokinetic need burden Interpretive gaps; range based exposure exposure body public information approaches relationship data biomarker-response biomarker-response perfluorooctanoic biomonitoring biomonitoring estimate estimate estimate general = Illustrate key reference put put concentration to to to to to with to to bounding develop develop PFOA physiologically and blood to to Used and modeling modeling modeling demonstrate information metabolite-exposure applicable Exemplified assessment assessment biomarker-response studies studies model studies subpopulation risk risk techniques toxicology urinary trichloroethylene; Examples Option exposure of develop = non-steady-state urine urine to and in in Case existing existing Bayesian animal epidemiology epidemiology pharmacokinetic pharmacokinetic pharmacokinetic worker TCE of of metabolite of from of of of of of of of humans humans ether; Interpretive Biomonitoring toxicity Comparison Use Use acid Use dose Use modeling Use in Use in Use excreted Use excreted Use Use pharmacokinetic Biomarker diphenyl and Major blood blood of in metabolites glyphosate carboxylic TCP monoester milk TCE PFOA lead mercury in metabolites lipid polybrominated Biomarker PBDEs breast Various Urinary Urinary Blood Serum Blood Blood Urinary Urinary metabolites Dioxin or Urinary = Overview PBDE 5-1 TABLE Chemical PBDE Organophosphates Glyphosate Permethrin TCE PFOA Lead Mercury Chlorpyrifos Phthalates Dioxin Styrene Abbreviations:
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From page 139... ...
Overview Establishing Reference Ranges Recent biomonitoring efforts in the United States and Europe have placed a high priority on establishing reference ranges. For example, a central purpose of the Third National Report on Human Exposure to Environmental Chemicals (CDC 2005)
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From page 140... ...
bNot calculated. Proportion of results below limit of detection was too high to provide valid result.
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From page 141... ...
Comparison with a Reference Population At the simplest level of interpretation of biomonitoring data, a biomarker concentration found in an individual or group under study is com
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From page 142... ...
(For discussion of an appropriate comparison population, see Chapter 4.) Figure 5-3 illustrates the distribution of biomarker concentrations in a generic reference population, expressed as cumulative frequency.
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From page 143... ...
1,132 100 (%) 75 frequency 50 e ulativ 25 Cum 0 ULV Biomarker Concentration FIGURE 5-3 Distribution of biomarker concentrations in generic reference population.
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From page 144... ...
Comparison with a reference range is useful for all applications in which a reference population is available. In the workplace, one may be able to identify high-exposure job categories by using biomonitoring results and evaluate whether measures to mitigate exposure are working to bring subgroups back toward the reference range.
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From page 145... ...
Box 5-1 presents a case example of the utility and limitations of reference ranges. Methodology, Principles, and Issues Ideally, reference ranges consist of biomonitoring values developed according to scientifically rigorous study design and quality-control procedures (see Chapter 4)
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From page 146... ...
There may be any number of reasons for this, such as more comparable lifestyle and exposures within a country than between continents and greater relevance for interpreting the opportunity for public-health intervention within a country. As shown in Figure 5-4, the rural population of this study (no occupational exposure)
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From page 147... ...
Interindividual variability in biomonitoring results will be a function of differences not only in exposure but also in pharmacokinetics with regard to metabolic and excretory clearance. Such host factors as age, genetic polymorphisms, clinical disease, medication and alcohol use, and nutritional status can affect pharmacokinetics.
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From page 148... ...
Keeping the proximity group separate would allow more direct comparisons with the reference population and more relevant interpretation of study results. Data Quality Ideally, reference ranges are developed from biomonitoring data that conform to the study design and to data-quality considerations (see Chapter 4)
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From page 149... ...
. In the same vein, the absence of reliable reference ranges limits the
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From page 150... ...
In appropriate cases, reference ranges established in other studies can provide helpful information. For example, in biomonitoring studies around hazardous-waste sites, industrial emission sources, and other point sources, it is not always possible to have a control population of sufficient size to yield an adequate reference or comparison range (Pirkle et al.
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From page 151... ...
Presenting that fact and other limitations is an essential aspect of communicating reference-range information to individuals, the general public, and organizational decision-makers -- a topic developed more fully in Chapter 6. ADAPTING WORKPLACE BIOLOGIC REFERENCE VALUES FOR INTERPRETING BIOMONITORING RESULTS Comparing Occupational Reference Values with Results of the National Health and Nutrition Examination Survey The use of reference ranges has been considered as a way to compare the exposure in an individual or group against a reference group, generally taken to mean a random sample of the general population.
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From page 152... ...
152 of % BEI 19.6 32.0 7.7 15.3 8.6 30.7 0.6 0.1 population ain m Concentrations creatinine creatinine of creatinine creatinine mg/g whereas of of mg/g of Observed percentile µg/g µg/L µg/L µg/L µg/g µg/L forms, and NHANES 95th 0.98 1.6 1.15 46 3.0 4.6 0.00289 0.00206 inorganic of to (2005) % BEI 5.5 6.0 2.5 5.3 1.9 4.7 -- - exposure to ACGIH by 2005)
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From page 153... ...
and BEI values. The BEI generally corresponds to the mean biomarker concentration that would result from inhalation-only exposure to the parent chemical at its TLV.
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From page 154... ...
In comparison, ingestion is often the principal exposure pathway for the general population. Assuming that an objective is to protect the general population from the same systemic toxic effects as workers, the importance of potentially different routes of entry must be examined.
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From page 155... ...
Those PK factors can modify the relationship between inhaled concentration and biomarker concentration, especially of metabolites detected in blood or urine. Sampling time is important.
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From page 156... ...
, so it would be a priori reasonable to consider extrapolation of the relationship between biomarker concentrations and those of their parent chemicals. For example, Tardif et al.
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From page 157... ...
Furthermore, although the BEIs are set to protect workers from deleterious effects of exposure to chemicals for a working lifetime, their toxicologic basis is often protection against acute effects that are not likely to be seen in the general population, whose members are exposed at much lower concentrations of the same substances and for whom long-term chronic effects are of greater concern. Although use of BEI or an adjusted BEI to evaluate biomonitoring results in the general population is problematic, the BEI derivation may provide useful information on the relationship between biomarker and external dose.
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From page 158... ...
factors do not appear to be appropriate for deriving biomarker concentrations for the general public. The database supporting the derivation of a BEI might be applicable to the development of human PK models that could be used to interpret biomonitoring results in the general population.
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From page 159... ...
Alternatively, traditional risk assessments may help to put biomonitoring results into a risk context. Those assessments combine animal toxicology studies with human exposure assessments to estimate risks to the general population and selected groups.
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From page 160... ...
160 orf manage ementg lic Social,, xts risk of Pub Conte Options of Mana y and m Economic or Risk elopmentv Control Substitute Inf oliticalP Management · · · aluation De Regulator Ev Health, and Risk Options Decisions assessment, Assessment. Actions and of olicyP and risk Risk a in nature the the ects is is the incidence ization: eff ust tain are population?
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From page 161... ...
. Pathway analyses were also reasonably complete so sources of human exposure could be identified.
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From page 162... ...
The application of biologic markers to environmental epidemiology provides an optimal approach for determining whether or not biomonitoring results indicate a health risk. Chapter 7 has recommendations for leveraging of existing or planned research to assess biomarker-response relationships in a cost-effective manner within ongoing epidemiologic study designs.
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From page 163... ...
, and the health significance of surpassing a particular "bright line" biomarker concentration. USING EXISTING RISK ASSESSMENTS FOR INTERPRETING BIOMONITORING DATA Interpretation of biomonitoring results can be enhanced by existing risk assessments of a specific chemical.
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From page 164... ...
· Collect sufficient biomarker data in animals to express the doseresponse relationship in key toxicology studies in terms of a biomarkerresponse relationship, in addition to an applied dose-response relationship. Using Biomarker-Led Approaches to Assess Risks Associated with Biomonitoring Results Option 1: Conversion of Biomonitoring Data to Exposure Dose with Human Pharmacokinetic Modeling In the sections below, four different cases for converting biomonitoring data to exposure dose using pharmacokinetic modeling are considered: lipid-soluble, bioaccumulative chemicals at steady state; lipid-soluble, bioaccumulative chemicals not at steady state; shorter-half-life chemicals at
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From page 165... ...
. As described below, these models can be used to relate biomonitoring results to exposure dose under some circumstances.
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From page 166... ...
For example, dioxin body burdens apparently increased in the early part of the 20th century and then declined over the last 2 decades. That pattern repre Lipid Content of Serum Biomarker concentration Lipid content of body Biomarker serum (SL, L/g lipid)
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From page 167... ...
These blood or tissue concentrations fluctuate slightly and in a regular pattern around the average concentration. If that is the case, blood concentrations may be relatively stable, and there is a potential to convert biomonitoring results into exposure estimates in a manner analogous to that described above for TCDD.
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From page 168... ...
Reasonable bounds on elimination rate and Vd could be used to calculate an upper end of daily dose that is still compatible with the biomonitoring results (for example, when both Vd and elimination rate are high)
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From page 169... ...
Case Example: Pharmacokinetic Calculations to Interpret Phthalate Urinary Biomarker Data. The previous descriptions focused on blood or adipose biomarker concentrations that were converted to body burden to yield estimates of daily dose based on chemical half-life.
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From page 170... ...
. Biomonitoring data have been converted to daily exposure dose (e.g., Koch et al.
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From page 171... ...
. A recent epidemiologic study of male postnatal measures in relation to maternal prenatal urinary concentrations of four phthalate metabolites suggests that biomarker results within the reference range are associated with altered male reproductive development (Swan et al.
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From page 172... ...
To correct for that, urinary biomonitoring results are often also expressed as per gram of creatinine (CDC 2005) on the assumption that the creatinine-excretion rate is less variable than the water-excretion rate.
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From page 173... ...
. If the intake of the metabolite from environmental sources is substantial in comparison with that of the parent chemical, as in the case of chlorpyrifos and TCP, the extrapolation of urinary biomarker concentration to parent-chemical exposure dose is uncertain.
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From page 174... ...
Studies which involved controlled human exposure to volatile organic compounds (VOCs) combined with repeated blood sampling have enabled researchers to evaluate the utility of PBPK models for interpreting biomonitoring results taken under non-steady-state conditions (Canuel et al.
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From page 175... ...
If one picks the peak internal concentration, the blood concentrations required to produce an effect will be higher, and the risk assessment will be less conservative than otherwise. Picking the lowest or highest internal concentration is an arbitrary decision, so it may be most practical to pick the average concentration achieved over 24 hours as a reasonable correlate to the toxic effects.
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From page 176... ...
. The internal LOAELs and NOAELs could then be used for comparison with biomarker data on humans.3 3It was not possible to construct PK models of the dosimetry in nursing pups, because of difficulties in estimating pup dose via lactation related to the likelihood of more rapid clear
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From page 177... ...
The PK models predicted both peak and AUC serum doses for the rat toxicicity end points. The human biomonitoring data are more likely to ance in these younger animals (Han 2003)
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From page 178... ...
There is no attempt to calculate exposure dose with pathway analysis, because the sources of human PFOA exposure are too uncertain. Instead, the biomonitoring data served as the sole source of human exposure information.
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From page 179... ...
A parallelogram approach similar to that derived from the work in the 1970s by Sobels (1977) could be used to extrapolate experimental biomarker results in animals to human health risk assessment as is now commonly done with exposure dose-response relationships (Sobels 1977; WHO 2001; Perera 1986; Sutter 1995)
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From page 180... ...
relationship, and the latter could be extrapolated to humans to interpret biomonitoring data. In the PFOA example described, biomarker measurements in animals were used to help to interpret human biomonitoring data.
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From page 181... ...
However, exposure assessment is also a critical component of risk assessment, since if risks are determined to be excessive, pathway analyses must be carried out to identify the major sources of exposure. This includes not only the immediate sources such as house dust, water, food, indoor air, or soil, but also the initial sources from which human exposure pathways originate (for example, industrial emissions, transportation sources, or consumer products)
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From page 182... ...
This could be overlaid with GIS maps of environmental data (for example, air or water pollution or distribution of waste sites) to determine whether biomonitoring results correspond to specific environmental sources.
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From page 183... ...
. Biomonitoring studies of PBDEs in breast milk found an increasing trend that correlated with societal use of flame retardants in consumer products during the 1980s and 1990s (Birnbaum and Staskal 2004)
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From page 184... ...
Large-scale biomonitoring studies illustrate the need for developing cumulative risk-assessment approaches for biomonitoring data because exposures are typically to mixtures rather than to single toxicants. An examination of the Third National Report on Human Exposure to Environmental Chemicals, for example,
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From page 185... ...
, may address some of the multiple-contaminant issues that are presented by population-based biomonitoring data. The committee recommends that CDC's National Reports on Exposure to Environmental Chemicals present population distributions showing the number of chemicals (and chemical classes)
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From page 186... ...
Those are all well-established fields, but only recently have they developed a focus on the interpretation of biomonitoring data. Therefore, there are a number of data gaps, uncertainties, and other limitations in developing risk assessments that can explain biomonitoring results.
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From page 187... ...
Increased attention to enrollment criteria in population biomonitoring studies and potential future uses of genetic markers indicative of metabolic capability can help to inform these kinds of uncertainty. The risk interpretation of biomonitoring results will tend to have additional uncertainties.
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From page 188... ...
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From page 189... ...
189 in to dose human risk reliable a human population. possible be species applicable to external estimate estimate general estimate across can can of can directly intervention transient not extrapolate results results too results to but exposure population.
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From page 190... ...
CONCLUSIONS This chapter identifies a variety of approaches for interpreting biomonitoring results, ranging from descriptive to risk-based. The descriptive approaches are useful as a first step in analyzing biomonitoring data, but they do not describe the level of risk.
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From page 191... ...
. · For persistent lipid-soluble compounds, conversion of blood or adipose tissue biomonitoring results to body burden and intake dose is feasible even with simple one-compartment models, although multicompartment physiologic models can provide a more flexible and improved tool for estimating dose.
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From page 192... ...
That requires obtaining animal PK data to support PBPK modeling or the collection of animal biomarker information in study designs that mimic key toxicology datasets. RECOMMENDATIONS Improved interpretation of biomonitoring results will require the expansion of the database typically available on many chemicals.
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From page 193... ...
· Incorporate metabolic-trait determination into biomonitoring studies (for example, genotyping or phenotyping of metabolic traits) to understand how the traits can affect biomonitoring results.
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From page 194... ...
2003. Second National Report on Hu man Exposure to Environmental Chemicals.
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From page 195... ...
2005. Third National Report on Human Exposure to Environmental Chemicals.
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From page 196... ...
1997. Lactational transfer of volatile chemicals in breast milk.
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From page 197... ...
2000. Human exposure estimates for phthalates.
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From page 198... ...
1995. Improving exposure assessment by moni toring human tissues for toxic chemicals.
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From page 199... ...
2005. Physiologically based pharmacokinetic modeling as a tool to interpret human biomonitoring data.
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From page 200... ...
2001. Estimation of cancer risk caused by environmental chemicals based on in vivo dose measurement.
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