11 Human Exposures and Body Burdens of Endocrine-Disrupting Chemicals
Antonia M. Calafat, P
HD , and Larry L. Needham, P
HD
C
ONTENTS1 Introduction and Overview
2 Using Biomonitoring in Assessment of Human Exposure to EDCs
3 Analytical Considerations for Biomonitoring 4 Selection of Biological Matrix
5 Selection of Biomarkers of Exposure 6 Biomonitoring Programs
7 Biomonitoring of EDCs (Phthalates, Phytoestrogens, BPA, and Halogenated Chemicals)
8 Summary
1. INTRODUCTION AND OVERVIEW
In today’s industrial societies, humans may be exposed to a wide variety of environ- mental chemicals, including those with potential endocrine-disruptive properties.
Although for many endocrine-disrupting chemicals (EDCs) the health significance of this exposure in humans is unknown, studies to investigate the prevalence of exposure are warranted. As often indicated in animal studies, exposure to EDCs may have poten- tially harmful health effects. To assess the effects of exposure, researchers have used three tools: exposure history/questionnaire information, environmental monitoring, and biomonitoring (i.e., measuring concentrations of the chemicals, their metabolites, or adducts in human specimens). Assessing exposure to most environmental chemicals of public health concern through a combination of biomonitoring data and indirect exposure measures is usually adequate. In this chapter, we present an overview on the use of biomonitoring in exposure assessment to EDCs using as examples phtha- lates, bisphenol A (BPA), and phytoestrogens, among others. We discuss some factors relevant to interpreting and understanding biomonitoring data, including selection of
From: Endocrine-Disrupting Chemicals: From Basic Research to Clinical Practice Edited by: A. C. Gore © Humana Press Inc., Totowa, NJ
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biomarkers of exposure and human matrices, and selection of toxicokinetic infor- mation. To link biomarker measurements to exposure, internal dose, or health outcome, additional information (e.g., toxicokinetics and inter- and intra-individual differences) is needed. We will not discuss assessing potential health risks from biomonitoring exposure data (human risk assessment) or risk management. For more information on this latter subject, see Chapter 12 in this book by Woodruff.
2. USING BIOMONITORING IN ASSESSMENT OF HUMAN EXPOSURE TO EDCS
Given their high production volumes and wide use, the probability of nonoccupa- tional human exposure to chemicals used in consumer products—including potential EDCs—is high. For the most part, little information exists about the extent of human exposure to many such chemicals, and their potential toxic health effects in humans are largely unknown. Because information on risk to human health from exposure to EDCs is limited, studies to investigate the prevalence of these exposures are warranted.
Exposure assessment in epidemiologic studies is, however, complex; under controlled conditions of dose–response (exposure or health effect) evaluations associated with animal studies, human exposures do not occur.
Historically, exposure assessments for EDCs and other environmental chemicals have relied on
• surveys of product use and food consumption,
• measurement of EDCs in food and various environmental media (e.g., air, water, and dust),
• estimates of human contact, and
• pharmacokinetic assumptions based on animal data.
In other words, to assess human exposure to EDCs, researchers have generally used indirect measures of exposure that combine environmental monitoring with exposure history and questionnaire data. Advances in analytical chemistry have made measuring trace levels of multiple environmental chemicals in biological tissues (i.e., biological monitoring or biomonitoring) possible and have contributed to increased use of biomon- itoring in exposure assessment (1,2). Biomonitoring data may in fact permit more accurate assessments of human exposure—concentrations of EDCs or their metabolites in biological matrices represent an integrative measure of exposure to these chemicals from multiple sources and routes. Therefore, using biomarkers for EDC exposure in combination with indirect measures of exposure are the most appropriate tools for exposure assessment.
Biomonitoring data on EDCs (i.e., internal dose measurements) can also be used
in risk assessment and risk management. For risk assessment, information on EDC
concentrations or their metabolites concentrations in biological media—as well as on
the EDC pharmacokinetics—are required to obtain exposure estimates. These estimates
are compared with toxicological parameters (e.g., NOAELs—no-observed-adverse-
effect limits), obtained generally from studies in animal (most frequently rodent)
models. Considerations relating to these hazard data include, among others, choice of
species, identification of critical endpoints, and relevance to humans. Biomonitoring in
risk management is also useful for ascertaining the effectiveness of risk management
practices; although, to develop effective risk management strategies, exposure pathway information is needed. However, discussing in detail the issues pertaining to biomoni- toring in risk assessment and management is beyond the scope of this chapter. Rather, we focus on biomonitoring for exposure assessment—we will not address biomoni- toring in risk assessment or risk management.
3. ANALYTICAL CONSIDERATIONS FOR BIOMONITORING Biomonitoring for assessing exposure to EDCs and other environmental chemicals generally requires measuring the analytes of interest at relatively low concentrations (e.g., at or below parts per billion). Therefore, biomonitoring must employ state-of-the- art analytical methods. These often include stable isotope-labeled internal standards and mass spectrometry (3).
Biological matrices are complex; they can also be difficult to obtain and may be available only in small amounts. Moreover, although environmental chemicals are normally present in the matrix at trace levels, other matrix components occur at higher concentrations. Thus, highly sensitive, specific, and selective multianalyte methods for the extraction, separation, and quantification of these chemicals must be developed (3).
Furthermore, when developing sampling, storage, and analysis protocols for biomon- itoring studies, researchers must consider (i) the chemical properties of the compounds of interest; (ii) the composition of the matrix; and (iii) the matrix’s potential effects on concentrations of selected analytes. Phthalates, a group of EDCs widely used as plasticizers in consumer goods and in personal care products (4), illustrate these considerations. Because some phthalates are environmentally ubiquitous, their direct measurement in biological specimens is subject to error; during sample collection, storage, and throughout the analytical measurement process, contamination can occur.
Consequently, because environmental exposure levels are normally much lower than those resulting from sampling contamination, human studies using phthalate diesters as biomarkers of exposure were limited to highly exposed populations (5–9). Phtha- lates are nonpersistent compounds that are rapidly hydrolyzed, metabolized, and excreted (10–13). To minimize contamination, the preferred biomonitoring approach is to measure urinary levels of phthalate metabolites (5,14). Phthalates can, however, be hydrolyzed to their monoesters by esterases present in milk (15), serum (16), and saliva (17,18). Other matrices such as amniotic fluid and meconium may also contain esterases. Concentration of phthalate monoesters in matrices other than urine can be used to estimate exposure, but only with safeguards in place to minimize contami- nation with phthalates during sampling, storage, and analysis. Otherwise, measured concentrations may include an unknown contribution from hydrolysis of contaminant phthalates by endogenous esterases. This phthalate example demonstrates that when developing protocols for biomonitoring sampling, storage, and analysis in addition to the chemical properties of the compounds of interest, the composition of the matrix and its potential effects on the concentrations of the selected analytes must be considered.
4. SELECTION OF BIOLOGICAL MATRIX
After exposure, environmental chemicals may enter the body. Once they reach the
blood systemic circulation, they can distribute into various body compartments, where
they can be in equilibrium with blood concentrations, secretion concentrations (e.g., milk),
or both. To compare concentrations in blood and other matrices, information is needed on partitioning these chemicals from blood into tissues (19).
Blood (or its components) and urine are the most common matrices for biomoni- toring. In general, the concentrations of persistent organic chemicals are measured in blood or blood products, whereas those of nonpersistent chemicals are most frequently measured in urine (20). Furthermore, traditional persistent lipophilic compounds [e.g., organochlorine pesticides, polychlorinated biphenyls (PCBs), and polychlorinated dibenzo-p-dioxins (PCDDs)] can partition from blood into adipose tissue and into milk for lactating women (21–24). Nonpersistent chemicals can also be found in milk. For example, phthalates and BPA, used to manufacture polycarbonate plastics and epoxy resins, have been found in human milk (15,25–28).
In the assessment of exposure to EDCs and other environmental contaminants, the use of unconventional matrices is becoming an increasingly important area of research (29,30). Urine is generally the matrix of choice for nonpersistent chemicals—
urinary concentrations of metabolites are higher than blood concentrations, urine is a relatively abundant matrix, and its collection is, in general, simple and nonin- vasive (20). In turn, blood is the preferred matrix for persistent compounds. Amounts of blood available for analysis are, however, normally limited, and blood collection is complicated and invasive (20). Depending upon the time period of concern for a particular exposure or health effect, alternative matrices to urine or blood may be preferable. For example, meconium and amniotic fluid may be used for assessing prenatal exposure to EDCs and other environmental chemicals (31–36). Although alter- native matrices may not be practical for large screening programs (vide infra), they may be very useful in specific situations. Some matrices are, for example, particularly useful in assessing exposure during fetal and early childhood life, when humans are most susceptible to potential adverse health effects of EDCs and other environmental chemicals. Amniotic fluid, cord blood, and meconium are promising matrices for monitoring prenatal exposures (31,32,36). Breast milk can be used to monitor neonatal exposures, and its analysis can also provide an estimate of fetal exposures to some chemicals (15,21–24,37–43).
5. SELECTION OF BIOMARKERS OF EXPOSURE
The extent of metabolism for nonpersistent chemicals can vary substantially.
Therefore, the choice of exposure biomarkers for nonpersistent chemicals is wider than for persistent chemicals, for which the biomarker of exposure is generally the parent compound. Nonpersistent EDCs can be partially or fully metabolized (e.g., phase I biotransformations) to increase their hydrophilic character. Both parent compound and phase I metabolites can be excreted unchanged or can undergo phase II biotransfor- mations and may be used as potential biomarkers of exposure.
Low-molecular-weight phthalates mostly metabolize to their hydrolytic
monoesters (10,12,44). High-molecular-weight phthalates, such as those with eight
or more carbons in the alkyl chain (e.g., di[2-ethylhexyl] phthalate, DEHP), metab-
olize to their hydrolytic monoesters, which can be further transformed to oxidative
products (11,13,44–48). Oxidative metabolites are more water-soluble than are the
corresponding hydrolytic monoesters. This explains, for a given phthalate, why the
urinary oxidative metabolite concentrations are higher than hydrolytic monoester
concentrations in human populations (49–54). Using hydrolytic monoesters of some high-molecular-weight phthalates as biomarkers of exposure may permit exposure comparison to the parent phthalate among studies. That said, however, using these metabolites as sole biomarkers to compare relative exposures to various phthalates can be misleading, especially when comparing monoester concentrations of high- and low-molecular-weight phthalates. Metabolism of the former results in more metabo- lites (11,13,44–48), thus decreasing the relative amounts of their hydrolytic monoester metabolites. To date, research on the oxidative metabolism of phthalates has been largely limited to phthalates with a defined chemical composition (e.g., DEHP). Most high-molecular-weight phthalates are complex mixtures of isomers (e.g., di-isononyl phthalate, DiNP). Their composition varies depending on the nature of the mixture of alcohols used for their synthesis, which, in turn, may vary with manufacturers.
Metabolism of isomeric high-molecular-weight phthalates will result in multiple hydrolytic and oxidative monoesters. In rats, hydrolytic monoesters represent a very small percentage of the phthalate dose (47,55). Although metabolic differences among species are possible, oxidative metabolites are the most abundant urinary metabolites of isomeric high-molecular-weight phthalates in humans (56). To assess properly the prevalence of exposure to these phthalates, research needs to focus on identifying and characterizing suitable oxidative metabolites. Until then, researchers will likely underestimate exposure to isomeric high-molecular-weight phthalates.
Oxidative metabolism is a common metabolic pathway in mammals. In a demograph- ically diverse sample of US adults, the frequency of detection and urinary concentration ranges of nonyl phenol (NP) were lower than those of BPA (57). Oxidative metabolism may have contributed, at least in part, to the relatively low urinary concentrations and frequency of detection of NP (57). Although ingested BPA is completely recovered in urine as BPA-glucuronide within approximately 24 h after exposure in humans (Volkel et al., 2002), only 10% of the ingested NP is excreted in the urine as NP or conjugated NP within 8 h—the rest are unidentified NP metabolites (58). If oxidative metabolism of NP prevails in humans as it does in animals, oxidative metabolites of NP may be the preferred biomarkers to assess exposure to NP rather than NP itself. Moreover, 4-n-NP, the measured NP isomer, represents a small percentage of the NP used in commercial mixtures (59). The point is that unless the most appropriate urinary biomarker(s) is used, exposure to NP may be underestimated.
Conjugation with -d-glucuronide and sulfate (phase II biotransformations) may reduce the bioactivity of nonpersistent EDCs and other chemicals while facilitating their urinary excretion. Phenols with ED properties, such as the phytoestrogen genistein, BPA, and parabens, are mostly excreted as conjugates (60–62). In these cases, the parent compound or its conjugated metabolites can potentially be used as biomarkers of exposure (62–64). Identifying and measuring the conjugated species of EDCs may, however, be challenging. Conjugated standards are not always readily available, and sensitive and accurate analytical methods are required to measure the concentrations of these species at trace levels. An alternate approach is to measure the total concentration of the compound (i.e., free plus conjugated species) after an enzymatic hydrolysis of the conjugates. This approach has been used in the measurement of EDCs such as phthalates, phytoestrogens, and BPA (14,56,62,64–72).
Individual variability to EDC exposure can result from changes in diet, daily lifestyle
activities, and physical condition. Although biomarkers of nonpersistent chemicals
in urine can accurately assess a person’s exposure at a single point in time, deter- mining exposure over an extended time period may require multiple measurements.
Therefore, optimizing the design of exposure assessment in epidemiologic studies requires information on the temporal variability of urinary levels of biomarkers of nonpersistent EDCs. To date, two published studies have addressed this issue. The first study documented relatively good reproducibility of phthalate monoester concentra- tions in two first-morning urine specimens collected for two consecutive days from 46 African-American women. Day-to-day intra-class correlation coefficients ranged from 0.5 to 0.8 (73). In the second report, the temporal variability in phthalate metabolite concentrations was evaluated among 11 men who provided up to nine urine samples each during a 3-month period (74). Although substantial day-to-day and month-to- month variability in each individual’s urinary phthalate metabolite concentrations existed, a single urine sample was moderately predictive of each subject’s exposure over 3 months, with sensitivities ranging from 0.56 to 0.74. Between- and within- subject variances as well as the predictive ability of a single urine sample differed among phthalate metabolites. This suggests that the most efficient exposure assessment strategy for a particular epidemiologic study may depend on the chemicals of interest.
Furthermore, a cross-sectional study of more than 2540 people in the USA showed variations in the population distributions of several phthalate metabolites depending on the time of day the urine samples were collected (75). These observations, along with the nonpersistent nature of phthalates, may reflect differences in the timing of exposure to phthalates during the day.
Because collecting 24-h urine samples is not practical for epidemiological studies, consideration should be given to standardizing the sample collection time. When the goal is to compare relative exposures to various chemicals across populations or among different studies, collecting first-morning urine samples is preferred. Nevertheless, studies designed to explore potential health risks of EDCs should not restrict sample collection to first-morning urine samples. The above data suggest that relevant exposure opportunities in the course of a day may be missed and exposure misclassified. At minimum, always record urine-collection timing.
6. BIOMONITORING PROGRAMS
Biomonitoring programs are useful for investigating human exposure to EDCs and other environmental chemicals. In the USA, the Centers for Disease Control and Prevention (CDC) annually conducts one of these programs. The National Health and Nutrition Examination Survey (NHANES) is designed to collect data on the health and nutritional status of the noninstitutionalized civilian US population (76). The survey includes a physical examination and collection of detailed medical history and biological specimens from participants. Although biological specimens are used mostly for clinical and nutritional testing, some can be used to assess exposure to environmental chemicals, including EDCs such as phthalates, phytoestrogens, PCBs, and dioxins.
Beginning with NHANES 1999, concentrations of selected chemicals in urine and
blood of NHANES participants, presented by age group, sex, and race/ethnicity,
have been reported in the National Reports on Human Exposure to Environmental
Chemicals (77,78). These reports provide the most comprehensive biomonitoring
assessment of the US population’s exposure to environmental chemicals. They may also help prioritize and foster research on the human health risks that result from exposure, which for many of the chemicals included in the reports are today largely unknown.
Data estimates from NHANES are probability-based and hence are representative of the US population. NHANES data can therefore be used to establish reference ranges for selected chemicals, provide exposure data for risk assessment (e.g., set intervention and research priorities, evaluate effectiveness of public health measures), and monitor exposure trends. Reference ranges can be used to assist epidemiologic investigations to correlate the levels to other NHANES parameters/measurements (including potential health effects) and to identify (i) populations with the highest exposures, (ii) potential sources/routes of exposure, and (iii) chemicals with highest prevalence/frequency (1).
Still, even a comprehensive program such as NHANES has limitations: persons under 1 year of age and older than 60 years of age are not included, and no data are collected on fetal exposures. Therefore, a pressing need exists for assessing exposure during critical periods of development—a period of increased susceptibility to the potential adverse effects of EDCs. Furthermore, NHANES by design provides only cross-sectional data;
it intentionally excludes population groups that might be highly exposed to various point sources but which could be examined to evaluate possible associations between high exposures and adverse health effects.
In Germany, German Environmental Surveys (GerESs) have since the mid-1980s conducted large-scale representative population studies for assessing general population exposure to environmental chemicals (e.g., lead, mercury, pentachlorophenol, polycyclic aromatic hydrocarbons (PAHs), cotinine). GerESs has used various tools, including questionnaires, human biomonitoring, and both indoor and outdoor environ- mental samplings (http://www.umweltbundesamt.de/survey-e/index.htm). Although previous surveys focused mostly on adult exposures, the ongoing GerES IV will also provide biomonitoring data on children between 3 and 5 years of age. For example, di(2-ethylhexyl) phthalate metabolites were measured in a subset of samples collected for the GerES IV pilot study (79).
7. BIOMONITORING OF EDCS (PHTHALATES, PHYTOESTROGENS, BPA, AND HALOGENATED CHEMICALS)
Since the late 1990s, both in Europe and in the USA, urinary concentrations of environmental chemicals, including EDCs or their metabolites, have been used as biomarkers to calculate human exposure among the general population to EDCs such as phytoestrogens, phthalates, and BPA (51,57,75,78,80,81).
In the USA, CDC reported the levels of seven urinary phthalate monoester metabo- lites in three subsets of NHANES participants (75,78,80). The first study included the analysis of a nonrepresentative call-back cohort of 289 urine samples, collected from adults during 1988–1994 for NHANES III (80). NHANES 1999–2000 and 2001–2002 (75,78) provided nationally representative, population-based, phthalate metabolite concentrations in urine for selected demographic groups in the USA.
Although the NHANES III and NHANES 1999–2002 data sets are not directly compa-
rable, the frequencies of detection of the phthalate monoesters were similar. The high-
molecular-weight phthalate monoesters (e.g., mono-2-ethylhexylphthalale (MEHP),
mono-n-octyl phthalate, mono-isononyl phthalate) were detected less frequently and at lower levels than the low-molecular-weight phthalates [e.g., mono-ethylphthalate (MEP), mono-butyl phthalate (MBP), and mono-benzyl phthalate (MBzP)]. Still, the mean and median concentrations of MEP, MBP, and MBzP were lower in the NHANES 1999–2002 than in the NHANES III subset population while the MEHP concentrations remained essentially unchanged. These findings may be related to the small size and nonrepresentative nature of the sampling for the NHANES III call-back cohort or to reduced exposure to some phthalates for the NHANES 1999–2002 population. The relatively low detection frequency of the high-molecular-weight phthalate monoesters may have been, at least in part, because, unlike the oxidative phthalate monoester metabolites, these hydrolytic metabolites may not be the most sensitive urinary biomarkers (vide infra). Nonetheless, these investigations, which confirmed that human exposure to selected phthalates is widespread, are also supported by studies assessing exposure to phthalates in specific groups of individuals (52–54,56,82–92).
Similarly, urinary concentrations of four isoflavones (genistein, daidzein, equol, and O-desmethylangolensin) and two lignans (enterolactone and enterodiol) were measured in three subsets of NHANES participants (78,93,94). In the first report, urinary concentrations of these six phytoestrogens were measured in 199 adult partici- pants of a call-back cohort for NHANES III (93). NHANES 1999–2000 and 2001–2002 each included over 2500 persons 6 years of age and older and provided nationally representative, population-based, urinary phytoestrogen concentrations for selected demographic groups in the USA. In these three studies, all phytoestrogens were frequently detected, and enterolactone was detected in the highest concentrations, with daidzein being the isoflavone found at the highest median concentrations (78,94). This research suggests that human exposure to phytoestrogens is widespread.
Another EDC of interest is BPA, used in the manufacture of polycarbonate plastic and epoxy resins, which in turn are used in commercial products such as baby bottles, as protective coatings on food containers, and for composites and sealants in dentistry.
BPA was measured in 394 archived urine samples, from a nonrepresentative call-back cohort of US adult residents, collected during 1988–1994 for NHANES III (57). BPA was detected in 95% of the samples examined at concentrations at or above 0.1 g/L of urine. The BPA concentration ranges were similar to those observed in other human populations outside the USA. Despite the relatively small size of the sample population and its nonrepresentative character, this study provided the first reference range of human internal dose BPA levels in a demographically diverse human population.
The study also confirmed widespread exposure to this compound in residents of the USA.
In addition to these examples of nonpersistent chemicals as potential EDCs, certain
persistent chemicals, such as PCBs, dibenzo-p-dioxins, and furans have been linked
with endocrine activity (95–97). The manufacturing of PCBs has been banned in most
countries since the 1970s. Nevertheless, because of these chemicals’ continued use
and environmental persistence, people continue to be exposed—although in general to
much lower amounts than a generation ago (98,99). For toxicological purposes, the
PCBs have been divided into three main classes: those containing no ortho chlorine
atoms (coplanar); those with one chlorine in the ortho position (mono-ortho); and those
containing chlorine substitution in two or more ortho positions. The first two classes
mentioned above are deemed to have dioxin-like activity and are discussed more
with the dioxin-related chemicals. Although PCBs generally enter the environment as commercial mixtures of congeners, the relative proportion of the various congeners changes because of environmental degradation and animal metabolism. In humans, generally the highest PCB concentrations are those with two or more ortho positions with chlorine substitution and to a lesser extent mono-ortho PCBs. In addition to the PCBs themselves, PCB-hydroxylated metabolites (OH-PCBs) have been reported to have endocrine-disrupting properties. The levels of the OH-PCBs are generally in the range of 10–20% of the PCB concentrations in blood lipids.
Exposure to PCBs is through the food chain, including high-fat foods and some fish and wildlife. Therefore, the highest human PCB exposures are generally found among high consumers of contaminated fish, wildlife, and dairy products (100–103).
People consuming these foods in the 1960–1970 decades have much higher internal concentrations of PCBs today than do present-day consumers (98). The reasons for this include much higher PCB environmental concentrations during the last century and also the bioaccumulation and long half-lives of many of the PCB congeners.
Today, most of the human toxicological concerns center on newborns, infants, and young adults. Because PCBs are lipophilic and because the within-person lipid blood concentration can vary widely (e.g., because of recently eating a high-fat meal), PCB blood concentrations are generally reported on a lipid-adjusted basis as well as on the more traditional whole-weight basis.
PCDDs, dibenzofurans, and PCBs have been measured in NHANES since 1999.
The NHANES 1999–2002 concentrations for these compounds were comparable with those reported in other countries (104,105) and were much lower than those reported in occupational settings. Most importantly, the NHANES 1999–2002 data demonstrate that human serum concentrations of these EDCs have decreased by more than 80%
since the 1980s (78,98,99). For example, in NHANES 2001–2002 (78), the 95th percentile concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)—one of the most potent of the dioxin-like chemicals—were 6.4 and 7.4 pg/g of lipid for women and non-Hispanic blacks, respectively. The concentrations in the remainder of the US population are most likely even lower than those reported for these two population groups.
Biomonitoring may also be valuable when a point source for exposure to low levels of EDCs is expected. For examples, exposure to BPA may occur following sealant placement. Leaching of BPA from the dental sealant into patients may be related to the quality of the sealant used (106). One important biomonitoring use is to assess exposures not specifically addressed in large-survey situations that could otherwise lead to biomarker concentrations well above the mean values found in the general population. For example, some phthalates [e.g., diethyl phthalate (DEP) and dibutyl phthalate (DBP)] can be used in enteric coatings for pharmaceutical agents, whereas DEHP is extensively used in medical tubing and devices. Therefore, use of certain medications (107,108) and medical interventions such as platelet donations (109,110) or intensive care therapeutic treatments (111–113) can result in exposures much higher than those experienced by the general population. Similarly, industrial accidents or other catastrophes may result in very high exposures to EDCs, among other chemicals.
One example is the exposure to TCDD after an explosion at a chemical plant near
Seveso, Italy, in 1976, that released a mixture of chemicals, including TCDD and 2,4,5-
trichlorophenol (114–116). Another is the accidental poisoning by PCB-contaminated
cooking oil in Yusho, Japan, and in Yucheng, Taiwan (117–124). Some of the concen- trations found in such cases are among the highest ever reported. Thus, these popula- tions can serve as benchmarks for comparison of human exposure and potential adverse EDC health effects (125–137).
8. SUMMARY
Biomonitoring provides a reliable estimate of internal dose. Comprehensive biomon- itoring programs, such as NHANES in the USA, must continue. However, under- standing of toxicokinetics of the environmental chemicals (e.g., distribution among body compartments and metabolism) and of their bioactivity at environmental exposure levels is required to properly interpret biomonitoring measurements. Age; diet; route, frequency, and magnitude of exposure; potential synergistic or antagonistic interactions among chemicals; and genetic factors, among others, are critical in determining health outcomes associated with exposure to environmental chemicals.
Because biomonitoring provides an integrated measure of exposure from all sources and routes, adequate sampling and storage protocols, and validated analytical methods that take into account both the nature of the matrix and the biomarkers must be used. For relatively lipophilic nonpersistent compounds (e.g., phthalates and alkyl phenols), formation of oxidative metabolites may be critical for facilitating their urinary excretion, and these oxidative metabolites may be the most appropriate biomarkers of exposure.
To maximize the impact of biomonitoring in public health, future research should focus on (i) identifying the compounds best suited for use as biomarkers, in particular those that may provide the greatest analytical sensitivity (e.g., oxidative metabolites), (ii) characterizing their potential bioactivity in humans, (iii) improving the under- standing of their toxicokinetics in different populations and with different doses with emphasis on fetal and neonatal exposures, when susceptibility to potential adverse health effects of environmental chemicals may be highest, and (iv) studying targeted populations with known source(s) of exposure to facilitate relating internal exposure to potential health effects.
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