Considerations on an Approach for Establishing a Framework for Bioactive Food Components

Bioactive food components have shown potential health benefits for more than a decade. Currently there are no recommended levels of intake [i.e., Dietary Reference Intakes (DRIs)] as there are for nutrients and fiber. DRIs for essential nutrients were based on requirements for each specific nutrient to maintain normal physiologic or biochemical function and to prevent signs of deficiency and adverse clinical effects. They were later expanded to include criteria for reducing the risk of chronic degenerative diseases for some nutrients. There are many challenges for establishing recommendations for intakes of nonessential food components. Although some nonessential food components have shown health benefits and are safe, validated biomarkers of disease risk reduction are lacking for many. Biomarkers of intake (exposure) are limited in number, especially because the bioactive compounds responsible for beneficial effects have not yet been identified or are unknown. Furthermore, given this lack of characterization of composition in a variety of foods, it is difficult to ascertain intakes of nonessential food components, especially with the use of food-frequency questionnaires designed for estimating intakes of nutrients. Various intermediary markers that may predict disease outcome have been used as functional criteria in the DRI process. However, few validated surrogate endpoints of chronic disease risk exist. Nonvalidated intermediary biomarkers of risk may possibly predict clinical outcomes, but more research is needed to confirm the associations between cause and effect. One criterion for establishing acceptable intermediary outcome indicators may be the maintenance of normal physiologic function throughout adulthood, which presumably would lead to reduced chronic disease risk. Multiple biomarkers of outcomes that demonstrate the same health benefit may also be helpful. It would be beneficial to continue to refine the process of setting DRIs by convening a workshop on establishing a framework for nonessential food components that would take into consideration intermediary biomarkers indicative of optimal health.     

Biomarkers of intermediate endpoints in environmental and occupational health

The use of biomarkers in environmental and occupational health is increasing due to increasing demands on information about health risks from unfavourable exposures. Biomarkers provide information about individual loads. Biomarkers of intermediate endpoints benefit in comparison with biomarkers of exposure from the fact that they are closer to the adverse outcome in the pathway from exposure to health effects and may provide powerful information for intervention. Some biomarkers are specific, e.g., DNA and protein adducts, while others are unspecific like the cytogenetic biomarkers of chromosomal aberrations (CA), sister chromatid exchanges and micronuclei (MN). The validation of biomarkers includes measurements of sensitivity and specificity of biomarkers and round robin tests to ensure reproducible protocols within different laboratories. The predictive value of biomarkers with respect to adverse health effect from the result of the measurement has been performed for the cytogenetic biomarkers showing a predictive value of high levels of CA and increased risk of cancer. The use of CA in future studies is, however, limited by the laborious and sensitive procedure of the test and lack of trained cytogeneticists. Less time consuming, but robust biomarkers, sensitive to environmental exposures are suggested. From the selection of developed biomarkers, the comet assay is highly sensitive to lifestyle exposures, often confounding the output, while MN in lymphocytes seem promising with respect to laboratory and health effect (cancer) validity. Also, new biomarkers exploiting the new 'omics' technologies are being developed. A number of ethical issues arise from the use of biomarkers with a predictive value aiming at respecting the autonomy of the study person in participation (only upon written informed consent and with obligations of withdrawal at any time), access to personal information (right to know and right not to know the study result) and securing proper data management (data protection to avoid misuse in employment, insurance, loaning and learning opportunities).     

Guidance values for the biomonitoring of occupational exposure. State of the art

Biomonitoring was developed for the assessment of the health risks from exposure to chemicals at work, and the approaches and concepts of biomonitoring are derived from such exposures. At present, biomonitoring is increasingly used also to assess exposure from the environment. Biomonitoring and assessment of external exposure are complementing activities, where the exposure assessments are much more widely applied, especially when the number of chemicals concerned is considered; environmental analysis also offers the distinct advantage of speciation analysis--which is very poorly developed for biomonitoring. Biomonitoring on the other hand provides information on exposure from all sources, and via all absorption routes, and considers also accumulation of the chemical in the body. Bio monitoring using exposure biomarkers thus consider interindividual differences in the absorption, while use of effec biomarkers ideally also considers interindividual differences in sensitivity. Few effect biomarkers, however, have been validated. The major challenges of biomonitoring are the development of monitoring methods, which are inexpensive enough to be applied at a frequency that makes possible meaningful biomonitoring of chemicals with a short half-time; development of exposure biomarker guidance values specific to individual species of different metals; ex pansion of the repertoire of validated effect biomarkers; and validation and application to effect monitoring of the omic technologies. Another major challenge is a reconsideration of the basis of biomonitoring action limits to reflec the change in the work place: Biomonitoring should be adapted to assist in the generation of a healthy workplace which is capable of attracting workers, and assist them to perform their work effectively--rather than just to guarantee absence of serious health effects.     

Use of biomarkers to indicate exposure of children to organophosphate pesticides: implications for a longitudinal study of children's environmental health

Because of their history of widespread use in the United States and unknown long-term health effects, organophosphate pesticides (OPs) are being considered as a chemical class of interest in planning for the National Children's Study, a longitudinal study of children's environmental health. The availability and appropriate use of biomarkers to determine absorbed doses of environmental chemicals such as OPs are critical issues. Biomarkers of OP exposure are typically measured in blood and urine; however, postpartum meconium has been shown to be a promising matrix for assessing cumulative in utero exposure to the fetus, and studies are currently in progress to determine the utility of using saliva and amniotic fluid as matrices. In this article, we discuss the advantages and disadvantages of the currently available OP exposure monitoring methods (cholinesterase inhibition in blood, pesticides in blood, metabolites in urine and alternative matrices); study design issues for a large, long-term study of children's environmental health; and current research and future research needs. Because OPs are rapidly metabolized and excreted, the utility of one-time spot measurements of OP biomarkers is questionable unless background exposure levels are relatively stable over time or a specific time frame of interest for the study is identified and samples are collected accordingly. Biomarkers of OP exposure can be a valuable tool in epidemiology of children's environmental health, as long as they are applied and interpreted appropriately.     

Molecular epidemiology studies on occupational and environmental exposure to mutagens and carcinogens, 1997-1999

Molecular epidemiology is a new and evolving area of research, combining laboratory measurement of internal dose, biologically effective dose, biologic effects, and influence of individual susceptibility with epidemiologic methodologies. Biomarkers evaluated were selected according to basic scheme: biomarkers of exposure--metabolites in urine, DNA adducts, protein adducts, and Comet assay parameters; biomarkers of effect--chromosomal aberrations, sister chromatid exchanges, micronuclei, mutations in the hypoxanthine-guanine phosphoribosyltransferase gene, and the activation of oncogenes coding for p53 or p21 proteins as measured on protein levels; biomarkers of susceptibility--genetic polymorphisms of genes CYP1A1, GSTM1, GSTT1, NAT2. DNA adducts measured by 32P-postlabeling are the biomarker of choice for the evaluation of exposure to polycyclic aromatic hydrocarbons. Protein adducts are useful as a biomarker for exposure to tobacco smoke (4-aminobiphenyl) or to smaller molecules such as acrylonitrile or 1,3-butadiene. Of the biomarkers of effect, the most common are cytogenetic end points. Epidemiologic studies support the use of chromosomal breakage as a relevant biomarker of cancer risk. The use of the Comet assay and methods analyzing oxidative DNA damage needs reliable validation for human biomonitoring. Until now there have not been sufficient data to interpret the relationship between genotypes, biomarkers of exposure, and biomarkers of effect for assessing the risk of human exposure to mutagens and carcinogens.     

Biomarker research in occupational health

OBJECTIVES: A variety of biomarkers have been used to study worker populations, and these studies have achieved different levels of success in the improvement of occupational health. METHODS: Successful application of biomarker research is dependent upon several important factors: ability to identify hazardous substances from the exposure to a variety of substances, relevance to the development of disease, and usefulness for health risk assessment. RESULTS: Besides the traditional biomarkers for exposure, biological effects, and health risk, new biomarkers for susceptibility and genome-wide responses are being used to improve our understanding of occupational health at a higher and, perhaps, more precise level. CONCLUSIONS: In addition, there is a continued need to develop and apply biomarkers that can be used to provide real-time detection of excessive exposure to hazardous substances in the workplace, especially from unexpected fugitive emissions. These topics are discussed in the review.     

Biomarkers of toluene diisocyanate exposure

Biomarkers are very useful tools when the metabolic fate of the compound or the etiology of a resultant disease is completely understood. They may contribute to confusion if it is not possible to distinguish between markers of exposure and markers of disease. Such is the case for biomarkers used in the assessment of diisocyanate exposure. Biomarkers for diisocyanate exposure result from both direct and indirect effects. Molecules such as hemoglobin, albumin, tubulin, glutathione, and laminin have been implicated as having been directly modified as a result of exposure to toluene diisocyanate (TDI). In addition, indirect biomarkers have included profiles of molecules such as antibodies, cytokines, cell accumulation or proliferation, and markers of oxidative stress. While a brief presentation of each of these markers is provided here, the focus is primarily on immunological markers as an example of the difficulties with using biomarkers in assessing diisocyanate exposure in general, and TDI specifically. Compiled data will be used to demonstrate where gaps exist in our understanding of how the results of measured biomarkers are used with regard to isocyanate exposure, and whether it may be possible to develop these tools to define thresholds between exposure and disease. Issues addressed include whether the marker represents a measure of exposure or disease, whether the methods are sufficiently uniform between labs to be able to compare between studies, and whether the ambiguities are the result of the complexity of the isocyanate reactivity in the biological system, or our inability to accurately measure the end point of the reactions.     

Harmonization of future needs for dermal exposure assessment and modeling: a workshop report

Dermal exposure assessment and modeling is still in early phases of development. This article presents the results of a workshop organized to harmonize the future needs in this field. Methods for dermal exposure assessment either assess the mass of contaminant that is transferred to the skin, or the transfer of contaminant through the skin. Models for dermal exposure are either knowledge-based or deterministic. Any method or model should be transparent, validated, and open to further development. Some (partly) validated and standardized methods are available for measuring or modeling permeation of the skin or of personal protective equipment (PPE). Further validation and standardization is necessary. More research is needed on permeation of dusts and aerosols and more realistic tests should be developed and used for PPE. Several methods have been developed to measure contamination of surfaces or skin, but they are not validated or standardized. A number of non-validated models exist to assess dermal exposure. A clear need exists for more studies of dermal exposure, regarding measurement methods, models and actual exposure levels. A running four-year European study will greatly expand the knowledge in this field. Simple tools to assess and control the risks of dermal exposure in small and medium sized enterprises are also needed. Increasing the general knowledge of practitioners (e.g., safety professionals, occupational hygienists and physicians) in the field of dermal exposure is a first requirement. Available data, for example, on the permeation of PPE, should be made more readily available, using modern information technology. When information on dermal exposure is gathered and stored, the core information needs are partly the same as those for inhalation exposure. Some elements of process and activity, substance and product or worker, specific for dermal exposure, have been suggested by the workshop.     

Biomarkers, screening and ethics

Rapid scientific advances, such as those in biomarker technology,have made a significant impact on the ethics and practice ofoccupational health. Biomarkers are extensively used in occupationalhealth practice. In the pre-employment stage, preventive orpredictive testing can be performed. Preventive testing aimsto avert accidents that may occur if a medically unfit workerundertakes a job that he is unable to perform. For safety sensitivejobs, routine testing of a worker's functional capacity in theactual job would suffice in most cases. However, a recentlyquotes application of a test is the screening for mutationsof the cardiac myosin-heavy chain and troponin genes among asymptomaticpersons with a family history of sudden death from hypertrophicobstructive cardiomyopathy. Predictive testing hopes to forecastthe risk of a worker developing an illness. The aims may vary.One aim may be to exclude a susceptible worker from workingin a hazardous environment. Another aim may be to avoid employmentof a worker who is likely to develop an illness which couldlead to higher employer health care costs. A pertinent questionto consider is whether the test undertaken is to benefit theindividual or to fulfil some administrative or financial need.Among exposed workers, screening may be conducted for biomarkersof exposure or effect. As the aim is to prevent the onset ofclinical illness, the physician must take responsibility forinitiating requests for screening. The appropriate responseto the effect of technical and societal advances on ethics isthe updating of ethical guidelines by the profession. However,in the context of unvalidated biomarkers being used for screening,it may be necessary to require a regulatory body to ensure thatthe tests are accurate and effective, and that they are notused to discriminate against individuals.     

Inter-individual variations of human mercury exposure biomarkers: a cross-sectional assessment

Background  

Biomarkers for mercury (Hg) exposure have frequently been used to assess exposure and risk in various groups of the general population. We have evaluated the most frequently used biomarkers and the physiology on which they are based, to explore the inter-individual variations and their suitability for exposure assessment.     

Using biomarkers to inform cumulative risk assessment

BACKGROUND: Biomarkers are considered the method of choice for determining exposure to environmental contaminants and relating such exposures to health outcomes. However, the association between many biomarkers and outcome is not direct because of variability in sensitivity and susceptibility in the individual. OBJECTIVES: We explore the relationship between environmental exposures and health outcomes as mitigated by differential susceptibility in individuals or populations and address the question "Can biomarkers enable us to understand and quantify better the population burden of disease and health effects attributable to environmental exposures?" METHODS: We use a case-study approach to develop the thesis that biomarkers offer a pathway to disaggregation of health effects into specific, if multiple, risk factors. We offer the point of view that a series or array of biomarkers, including biomarkers of exposure, biomarkers of susceptibility, and biomarkers of effect, used in concert offer the best means by which to effect this disaggregation. We commence our discussion by developing the characteristics of an ideal biomarker, then give some examples of commonly used biomarkers to show the strengths and weaknesses of current usage. We follow this by more detailed case-study assessment outlining the state-of-the-science in specific cases. We complete our work with recommendations regarding the future use of biomarkers and areas for continued development. CONCLUSIONS: The case studies provide examples of when and how biomarkers can be used to infer the source and magnitude of exposure among a set of competing sources and pathways. The answer to this question is chemical specific and relates to how well the biomarker matches the characteristics of an "ideal" biomarker-in particular ease of collection and persistence. The use of biomarkers in combination provides a better opportunity to disaggregate both source and pathway contributions.     

Screening and testing for endocrine disruption in fish-biomarkers as "signposts," not "traffic lights," in risk assessment

Biomarkers are currently best used as mechanistic "signposts" rather than as "traffic lights" in the environmental risk assessment of endocrine-disrupting chemicals (EDCs). In field studies, biomarkers of exposure [e.g., vitellogenin (VTG) induction in male fish] are powerful tools for tracking single substances and mixtures of concern. Biomarkers also provide linkage between field and laboratory data, thereby playing an important role in directing the need for and design of fish chronic tests for EDCs. It is the adverse effect end points (e.g., altered development, growth, and/or reproduction) from such tests that are most valuable for calculating adverseNOEC (no observed effect concentration) or adverseEC10 (effective concentration for a 10% response) and subsequently deriving predicted no effect concentrations (PNECs). With current uncertainties, biomarkerNOEC or biomarkerEC10 data should not be used in isolation to derive PNECs. In the future, however, there may be scope to increasingly use biomarker data in environmental decision making, if plausible linkages can be made across levels of organization such that adverse outcomes might be envisaged relative to biomarker responses. For biomarkers to fulfil their potential, they should be mechanistically relevant and reproducible (as measured by interlaboratory comparisons of the same protocol). VTG is a good example of such a biomarker in that it provides an insight to the mode of action (estrogenicity) that is vital to fish reproductive health. Interlaboratory reproducibility data for VTG are also encouraging; recent comparisons (using the same immunoassay protocol) have provided coefficients of variation (CVs) of 38-55% (comparable to published CVs of 19-58% for fish survival and growth end points used in regulatory test guidelines). While concern over environmental xenoestrogens has led to the evaluation of reproductive biomarkers in fish, it must be remembered that many substances act via diverse mechanisms of action such that the environmental risk assessment for EDCs is a broad and complex issue. Also, biomarkers such as secondary sexual characteristics, gonadosomatic indices, plasma steroids, and gonadal histology have significant potential for guiding interspecies assessments of EDCs and designing fish chronic tests. To strengthen the utility of EDC biomarkers in fish, we need to establish a historical control database (also considering natural variability) to help differentiate between statistically detectable versus biologically significant responses. In conclusion, as research continues to develop a range of useful EDC biomarkers, environmental decision-making needs to move forward, and it is proposed that the "biomarkers as signposts" approach is a pragmatic way forward in the current risk assessment of EDCs.     

The biomarkers detecting early changes in the human organism exposed to occupational carcinogens

Epidemiological studies and clinical data confirm that occupational exposure to carcinogenic agents plays an important role in cancer etiology. Recent tremendous progress in understanding of the mechanisms of carcinogenesis, and also introduction of new tests to recognize changes occurring in the exposed organism have made it possible for the occupational medicine to detect the earliest cancer stages which occur during the latent phase of the disease. Detecting pre-neoplastic changes which precede an overt form of cancer and identification of measurable indicators of those changes has been one of the fundamental aims of molecular biology research. Biomarkers may serve as a research tool which makes it possible to achieve this aim. Suitably selected biomarker sets can provide information on the extent of the exposure to carcinogenic agents (biomarkers of exposure), detect early changes produced by the agents in the exposed organism (biomarkers of effects), and identify people with particularly high cancer risk (biomarkers of susceptibility). It will soon be possible to use molecular biomarkers, capable of detecting increased cancer risk at the molecular level of cell structure, in prophylactic action intended to reduce cancer incidence. Molecular biomarkers are capable of recording very early health effects of exposure to carcinogens, thus making it possible to determine cancer risk at a very early stage of cancer development.     

Biomarkers for assessing reproductive development and health: Part 1--Pubertal development

The proposed National Children's Study has helped raise awareness of the issues related to children's health and the importance of monitoring the growth and development of children from preconception through adulthood. Many genetic predispositions can adversely impact the normal development process, and various environmental exposures have been linked to adverse reproductive health in rodent models and a small number of accidental human exposures. To monitor reproductive health and identify adverse effects at the earliest possible juncture, investigators must develop a network of biomarkers covering all stages and aspects of reproductive development and function. Biomarkers are biological indicators that can be measured repeatedly and are informative on one or more aspects of biological development or function. They can range from the anatomical level down to the molecular level and may provide information on the nature of an exposure, the effect of an exposure, or the susceptibility of individuals or populations to the toxic effects of an exposure. In theory, biomarkers can be used to monitor a wide variety of conditions and responses ranging from abnormal development to early indicators of late-onset disease. The main stumbling block with this theory has been finding appropriate biomarkers for particular conditions and exposures. Such biomarkers must be easily accessible, robust, and sensitive. Ideally, they will be expressed across a large section of the population, and can be monitored quickly, easily, conveniently, and with minimal cost. In this review, we discuss some of the current and emerging biomarkers of human pubertal development.     

Executive summary--Biomarkers of Nutrition for Development: Building a Consensus

The ability to develop evidence-based clinical guidance and effective programs and policies to achieve global health promotion and disease prevention goals depends on the availability of valid and reliable data. With specific regard to the role of food and nutrition in achieving those goals, relevant data are developed with the use of biomarkers that reflect nutrient exposure, status, and functional effect. A need exists to promote the discovery, development, and use of biomarkers across a range of applications. In addition, a process is needed to harmonize the global health community's decision making about what biomarkers are best suited for a given use under specific conditions and settings. To address these needs, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services, organized a conference entitled "Biomarkers of Nutrition for Development: Building a Consensus," which was hosted by the International Atomic Energy Agency. Partners included key multilateral, US agencies and public and private organizations. The assembly endorsed the utility of this initiative and the need for the BOND (Biomarkers of Nutrition for Development) project to continue. A consensus was reached on the requirement to develop a process to inform the community about the relative strengths or weaknesses and specific applications of various biomarkers under defined conditions. The articles in this supplement summarize the deliberations of the 4 working groups: research, clinical, policy, and programmatic. Also described are content presentations on the harmonization processes, the evidence base for biomarkers for 5 case-study micronutrients, and new frontiers in science and technology.     

砷致健康危害生物标志物研究进展

尿、发、指(趾)甲中砷水平可以反应短期砷接触内剂量,可作为人体内灵敏有效的砷暴露标志物.长期慢性砷接触可以诱发皮肤色素代谢异常和掌跖角化等典型的皮肤病变,尿中MMA(V)可认为是暴露的生物有效剂量.活性氧和抗氧化能力、炎性分子基因表达、外周血淋巴细胞微核和姊妹染色单体互换和染色体畸变是无机砷摄入的早期生物效应标志物.砷易感性标志物包括DNA修复酶、氧化和抗氧化酶、氧化应激相关酶以及异物代谢酶基因组多态性.砷对健康的危害是由于基因组不稳定性和氧化应激等毒理机制而导致的基因-基因、基因-环境交互作用的慢性复杂的渐进性损害.     

Biomarkers of semen in the vagina: applications in clinical trials of contraception and prevention of sexually transmitted pathogens including HIV

Biomarkers of vaginal exposure to semen, long used in forensic medicine, are now becoming important in the development of vaginal microbicides to prevent HIV/STIs and the development of contraceptives. Semen biomarkers could help evaluate the safety of a new physical or chemical barrier, give preliminary indication of the effectiveness of physical barriers such as diaphragms or condoms, and provide information on unprotected intercourse among participants in a clinical trial who have been advised to use condoms. Candidate biomarkers of semen exposure fall into two broad categories: (1) biomarkers of seminal plasma, among which prostate-specific antigen (PSA) is the best characterized; and (2) biomarkers of spermatozoa and other cells present in semen. This paper, authored by a working group of investigators performing research in the field of semen biomarkers, summarizes the characteristics of an ideal semen biomarker, reviews preclinical and clinical data on existing and potential biomarkers, and outlines the steps that should be carried out to develop an improved biomarker of semen exposure.     

Surrogate endpoints and emerging surrogate endpoints for risk reduction of cardiovascular disease

This article reviews surrogate endpoints and emerging biomarkers that were discussed at the annual "Cardiovascular Biomarkers and Surrogate Endpoints" symposium cosponsored by the US Food and Drug Administration (FDA) and the Montreal Heart Institute. The FDA's Center for Food Safety and Applied Nutrition (CFSAN) uses surrogate endpoints in its scientific review of a substance/disease relationship for a health claim. CFSAN currently recognizes three validated surrogate endpoints: blood pressure, blood total cholesterol, and blood low-density lipoprotein (LDL) concentration in its review of a health claim for cardiovascular disease (CVD). Numerous potential surrogate endpoints of CVD are being evaluated as the pathophysiology of heart disease is becoming better understood. However, these emerging biomarkers need to be validated as surrogate endpoints before they are used by CFSAN in the evaluation of a CVD health claim.     

Biomarkers of ambient air pollution and lung cancer: a systematic review

The association between ambient air pollution exposure and lung cancer risk has been investigated in prospective studies and the results are generally consistent, indicating that long-term exposure to air pollution may cause lung cancer. Despite the prospective nature and consistent findings of these studies, causality assessment can benefit from biomarker research. In the present systematic review, we assess the contribution of intermediate biomarkers in epidemiological studies, to ascertain whether their measurement reinforces causal reasoning. We have reviewed 524 papers which described the relationships between ambient air pollution and biological markers of dose and early response. The evidence for each marker was evaluated using assessment criteria which rate a group of studies from A (strong) to C (weak) on amount of evidence, replication of findings, and protection from bias. Biomarkers that scored A or B for all three criteria are included here. The markers that fulfilled the inclusion criteria are: 1-hydroxypyrene, DNA adducts, chromosomal aberrations, micronuclei, oxidative damage to nucleobases, and methylation changes. These biomarkers cover the whole spectrum of disease onset and progression from external exposure to tumour formation and some have also been suggested as risk predictors of future cancer, reinforcing causal reasoning. However, methodological issues such as confounding, publication bias and use of surrogate tissues instead of target tissues in studies on these markers are of concern. The identified biological markers have potential to shed light on the pathways of carcinogenesis, thus defining the association more clearly for public health interventions.     

Comparative evaluation of absorbed dose estimates derived from passive dosimetry measurements to those derived from biological monitoring: validation of exposure monitoring methodologies

Passive dosimetry (PD) methods for measuring and estimating exposure to agricultural workers (i.e., persons handling agricultural chemicals and working in treated crops) have been in use since the 1950s. A large number of studies were conducted in the 1950s through 1970s to characterize exposure. Since the 1980s quantitative dermal PD methods are used in conjunction with inhalation PD methods to measure whole-body exposure. These exposure or absorbed dose estimates are then compared to "no effect" exposure levels for hazards identified in toxicology studies, and have become the standard for risk assessment for regulatory agencies. The PD methods used have never been validated. Validation in the context of human exposure monitoring methods means that a method has been shown to measure accurately a delivered dose in humans. The most practical alternative to isolating parts of the body for validating recovery methods is to utilize field exposure studies in which concurrent or consecutive measurements of exposure and absorbed dose have been made with PD and biomonitoring in the same cohorts of individuals. This ensures that a direct comparison can be made between the two estimates of absorbed dose, one derived from PD and the other from biomonitoring. There are several studies available (published and proprietary) employing both of these approaches. Reports involving 14 concurrent or consecutive PD-biomonitoring studies were quantitatively evaluated with 18 different methods of application or reentry scenarios for eight different active ingredients for which measured human kinetics and dermal absorption data existed. This evaluation demonstrated that the total absorbed dose estimated using PD for important handler and reentry scenarios is generally similar to the measurements for those same scenarios made using human urinary biomonitoring methods. The statistical analysis of individual worker PD:biomonitoring ratios showed them to be significantly correlated in these studies. The PD techniques currently employed yield a reproducible, standard methodology that is valid and reliably quantifies exposure.