Human Biomonitoring for Environmental Chemicals (2006) / Chapter Skim
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4 Considerations in the Design of Biomonitoring Studies
4 Considerations in the Design of Biomonitoring Studies
Pages 84-131
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From page 84... ...
. Detailed discussion of the scientific approaches for each of them is beyond the scope of this report, but there are some issues in the design, conduct, and analysis of all biomonitoring studies for which the committee deemed review of scientific practice crucial to the further development of the field.
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From page 85... ...
Figure 4-1 presents a schematic diagram of the various considerations in the design of a biomonitoring study addressed in the chapter as well as Chapters 5 and 6 and their relationship to one another. The four stages of any biomonitoring study are study design, study conduct, data analysis, and communication and implementation of results.
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From page 86... ...
, but because it was the committee's intent to prompt readers to consider these issues as intrinsic in the design of biomonitoring studies. STUDY DESIGN Design of a biomonitoring study incorporates several key components, including consideration of the study hypothesis, the properties of the bio
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From page 87... ...
So, for instance, in measuring chemicals in the workplace, the required limit of detection may be much higher than that needed for assessing environmental exposures in the general population. Figure 4-2 illustrates the contribution of environmental and occupational exposure to biomarker concentrations and the effect of a method's limit of detection, LOD (or limit of quantification)
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From page 88... ...
others where the endogenous contribution to a biomarker concentration exceeds that of community exposure to the parent compound. Specificity The biomarker should be specific for the chemical or metabolites of interest; that is, it needs to be an unambiguous marker of exposure.
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From page 89... ...
A sample should be readily obtainable, storable for a certain period, and capable of being analyzed. (More information on the choice of matrix and logistics of sample collection and processing will be presented later, under "Sample Collection and Processing.")
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From page 90... ...
The measure usually referred to is the half-life, which reflects both the affinity of the chemical for the biologic matrix and the efficiency of metabolic or elimination processes. Knowledge of half-life is important for several reasons, including its use in determining sampling time (Bernard 1995)
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From page 91... ...
Since the biomarker concentration decreases with time, knowledge of the time lapsed between exposure and sampling is needed to calculate the dose correctly. In practice, it is usually difficult, if not impossible, to tell with any accuracy when exposure occurred.
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From page 92... ...
, in which case a pseudo-steadystate is reached so that the biomarker concentrations reflects continuing average exposure with little influence from sporadic exposure peaks, age, or migration of people to the area under study. The example given here is representative of many environmental pollutants that are ingested in food.
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From page 93... ...
93 Daily days.
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From page 94... ...
. Squeezing a polyphasic pharmacokinetic behavior into a one-compartment model by assuming a single half-life may lead to negligible errors for some chemicals and serious misinterpretation of biomarker concentrations for others.
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From page 95... ...
Polling organizations go to considerable lengths to achieve just that; the three waves of biomonitoring performed by CDC in the National Health and Nutrition Examination Survey (NHANES) are a model effort from this perspective.
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From page 96... ...
When biomonitoring results are presented in relation to each of those characteristics, valuable insights may be gleaned regarding sources of exposure and factors that modify exposure. Covariates of particular importance are factors related to socioeconomic status (SES)
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From page 97... ...
But this possibility cannot be meaningfully evaluated without detailed knowledge of the relevant characteristics for each subject in biomonitoring or epidemiologic studies that use biomarkers. The committee recommends that investigators, including CDC, that conduct surveys of biomarkers in the population should routinely collect detailed information about SES, lifestyle, and other cofactors on each subject and routinely present results organized so as to address the question of whether biomarker concentrations vary as a function of each.
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From page 98... ...
The distribution of such substances depends on the amount of and blood flow to adipose tissue in the body. Body build and obesity depend on genetic factors, dietary habits, and exercise, all of which may vary between ethnic and socioeconomic groups and geographic regions.
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From page 99... ...
The influence of pharmacokinetic factors -- such as physical exercise, body build, diet, and polymorphisms -- on interindividual and intraindividual variability in biomarker concentration depends on the physicochemical characteristics of the chemicals. The relationships are often difficult to describe with simple, general rules.
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From page 100... ...
For example, if a biomonitoring study reveals that the internal dose of a population living near a polluting plant has reached intolerable levels, a policy decision might be made to close the plant or move neighboring residents. It is crucial that health, economic, regulatory, and other ramifications for all potential constituencies be considered by both study designers and study subjects before the study begins.
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From page 101... ...
In other situations (such as for group III or IV substances) , the health implications of biomarker concentrations for an individual may be unclear, but possible actions are obvious, such as when chemical exposure can be easily reduced by individuals' actions.
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From page 102... ...
in studies that use high-output, high-throughput technologies. For studies that develop a biomarker, researchers should provide as much information as possible on the biomarker and its parent chemical.
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From page 103... ...
But the fact that a urinary metabolite is a "biologic" substance sometimes creates far different legal and ethical obligations from its equivalent "chemical" counterpart. A biomarker concentration considerably below guideline levels might have to be declared to public-health authorities, whereas there is no such obligation regarding air concentrations even just below legal limits.
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From page 104... ...
Project and communication goals are 2Some people might prefer the term audience(s) for those considered in biomonitoringproject design, and those targeted for messages about biomonitoring results (Chapter 6)
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From page 105... ...
However, most biomonitoring research will have eventual applications; researchers who think they will not need to communicate and thus ignore constituency assessment are likely to be unpleasantly surprised. Practical Issues First, biomonitoring funders should require communication planning in any application for funding.
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From page 106... ...
on project design. Third, the often tense political and social context in which biomonitoring studies are conducted (see Chapter 4 introduction)
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From page 107... ...
Second, although there is some work on design of analytic-deliberative processes, it is recognized that much more research is needed to understand how to improve their functioning, particularly as the scientific proportion of issue analysis -- as in biomonitoring studies -- increases (Stern and Fineberg 1996)
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From page 108... ...
also offer suggestions for providing government agencies useful communication evaluations. Practical Issues Quality assurance and quality control of biomarker data get far more attention than whether biomonitoring communication goals are achieved and why (Balch and Sutton 1995)
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From page 109... ...
Knowing messages and methods of communication that work, and why, would be invaluable to projects with similar communication goals or biomonitoring data (e.g., see Schulte et al. 1997 on evaluating notifications of individual results)
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From page 110... ...
STUDY CONDUCT Execution of the study consists of collecting the biologic samples (including considerations regarding sampling time and quality assurance, depending on the matrix -- such as blood or urine -- used) , transporting them from the field to the laboratory, and processing them in the laboratory.
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From page 111... ...
Finally, in older children and adults, the amount of urine is no longer a limiting factor, and the main focus in consideration of study design shifts to the timing of collection. For example, a morning void may be needed to acquire a more concentrated sample for low-level chronic exposures, and the end of the work shift can be more appropriate if the goal of the study is to monitor occupational exposure.
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From page 112... ...
112 Adults + + + + Children 5-18 years old + Children 0-5 years old +++ +++ +++ +++ +++ +++ +++ +++ + Delivery + + Life of Stages Fetal Period o N es/ Invasive Y Y N N N N N N N N Y+ Y Y N N N out Studies swab falling or or collection container diapers cotton container container cut prick delivery or diapers or sterile pipette (mother) after sterile sterile extraction after cups attachment into prepared in in or from postmortem Biomonitoring plastic or tap pump cord loss for container Procedure Venipuncture Drained from Collection Sterile specially Spirometer In Clippings Collected after Collected Amniocentesis Biopsy Spinal Breast Cup Container Matrices 4-2 fluid air tissue blood milk marrow TABLE Collection Matrices Blood Cord Urine Saliva Expired Hair Fingernails Teeth Meconium Amniotic Adipose Bone Breast Semen Feces
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From page 113... ...
. Many other matrices can be used for biomonitoring studies, including saliva, breast milk, hair, fingernails, meconium, bone marrow, and feces (Table 4-2)
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From page 114... ...
Quality Assurance for Sample Collection To ensure the quality of specimens for current and future use, most researchers develop protocols for collecting, shipping, processing, and banking samples -- standard operating procedures (SOPs) (Heinrich-Ramm et al.
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From page 115... ...
From Field to Laboratory Depending on the type of monitoring study, sample collection can take place in the clinic, in the field office, or even in the home of a participant. Each scenario imposes specific requirements and limitations on the type, volume, and potential use of a sample.
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From page 116... ...
. That different components of blood must be stored at different temperatures should be considered in the study design.
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From page 117... ...
. Laboratory Analysis Laboratory analysis of human specimens is an integral part of any biomonitoring study.
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From page 118... ...
For example, an occupational physician seeking to compare concentrations of a chemical in blood samples drawn from a few employees with national reference values will be concerned about interlaboratory variability but will not necessarily require a very low limit of detection. Alternatively, an epidemiologist conducting a study of an "unexposed" population may require a low limit of detection to classify individual exposure status but, if all samples are analyzed in a single laboratory, may be less concerned about interlaboratory variability introduced by methodologic differences.
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From page 119... ...
Thus, depending on study design, the validation specimens might be analyzed by multiple analysts using different instruments on different days. After completion of the validation sequence (which often requires analysis of hundreds of specimens)
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From page 120... ...
The problem may become more acute as the list of chemicals with well-established population-based reference ranges continues to be expanded by the NHANES program, facilitating the interpretation of patient values. Selecting a laboratory and an analytic method that can provide data of sufficient quality for their intended purpose can be difficult.
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From page 121... ...
For example, an occupational physician faced with a specific biomarker concentration in a specific worker is faced with the inferential question of whether the worker belongs to the group of workers "exposed" or "not exposed." The inference will be drawn by bringing in other factors, such as a careful work history. If the same physician is interested in the worker's result for a study of occupational disease, the target of inference is different, and different statistical analyses will be required.
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From page 122... ...
Statisticians have developed a useful terminology for patterns of missingness. Longitudinal data are usually analyzed with fairly complicated statistical models, such as mixed-effect regression models, generalized estimating equations, and logistic-regression models.
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From page 123... ...
It is usual whenever biologic samples are obtained in medical practice or in any health encounter for results to be expressed in relation to "normal." In fact, a relationship to "normal" is the question almost every subject asks first when presented with such information. For biomonitoring results, it is a generally meaningless question -- "normal" for human-made chemicals or chemicals that did not enter the environment except for human activity, is actually zero.
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From page 124... ...
This chapter has provided guidelines for the conduct of biomonitoring studies, including study design, study conduct, and data analysis. Because not all biomonitoring studies are conducted with the same rigor, it is important that the guidelines presented be followed to ensure, to the extent possible, that biomonitoring studies will lead to the identification of chemicals that are causing risks or health effects, will provide information on exposure pathways and health effects to guide future control efforts, and will avoid anxiety or apathy about chemicals where personal or societal risk appears not to warrant that reaction.
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From page 125... ...
to the model, additional features may be examined including variability in exposure pattern and intra- and interindividual variability in pharmacokinetic determinants. · Investigators, including CDC, that conduct surveys of biomarkers in the population should routinely collect detailed information about SES, lifestyle, and other cofactors on each subject and should routinely present results organized in a way that addresses the issue of whether biomarker concentrations vary as a function of each.
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From page 126... ...
However, federal agencies and statutes, such as CDC, the National Institute of Standards and Technology, and statutes such as CLIA, could play important roles in improving the overall quality of biomonitoring laboratory data and their utility in health-related applications. · NHANES and other studies are rapidly expanding the list of chemicals for which population-based reference values are available.
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From page 127... ...
Standardization and harmonization are particularly important for international collaboration. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists)
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From page 128... ...
Environ. Health Perspect.
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From page 129... ...
2005. Research Ethics and Human Biomonitoring Research.
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From page 130... ...
2005. Application and Design Issues in Human Biomonitoring.
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From page 131... ...
2004. Urinary levels of seven phthalate metabolites in the U.S.
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