ToxSci Advance Access originally published online on June 19, 2006
Toxicological Sciences 2006 93(1):3-10; doi:10.1093/toxsci/kfl042
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FORUM |
Strategic Biomonitoring Initiatives: Moving the Science Forward
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* Institute of Occupational, Social, and Environmental Medicine, University of Erlangen, D-91054 Erlangen, Germany; ExxonMobil Biomedical Sciences, Inc., Annandale, New Jersey 08801; Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205; ILSI Health and Environmental Sciences Institute, Washington, DC 20005; ¶ Centers for Disease Control and Prevention, Atlanta, Georgia 30341; || The Procter and Gamble Company, Cincinnati, Ohio 45253; ||| National Exposure Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and |||| National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
1 To whom correspondence should be addressed at ILSI Health and Environmental Sciences Institute, One Thomas Circle, NW, Ninth Floor, Washington, DC 20005. Fax: (202) 659-3617. E-mail: ndoerrer{at}hesiglobal.org.
Received April 14, 2006; accepted June 9, 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSTRATEGIC BIOMONITORING...CASE STUDY: METHYL EUGENOLDISCUSSIONABOUT HESIREFERENCES |
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Biomonitoring programs in the United States and Europe demonstrate the vast array of data that are publicly available for the evaluation of exposure trends, identification of susceptible populations, detection of emerging chemical risks, the conduct of epidemiology studies, and evaluation of risk reduction strategies. To cultivate international discussion on these issues, the ILSI Health and Environmental Sciences Institute convened a scientific session at its annual meeting in January 2006 on "Integration of Biomonitoring Exposure Data into the Risk Assessment Process." This Forum paper presents perspectives from session speakers on the biomonitoring activities of the Centers for Disease Control and Prevention, the U.S. Environmental Protection Agency, the National Research Council Committee on Human Biomonitoring for Environmental Toxicants, the German Commission on Human Biomonitoring, and the Health and Environmental Sciences Institute Biomonitoring Technical Committee. Speakers noted that better estimates of biological concentrations of substances in the tissues of human populations can be combined with other exposure indices, as well as epidemiological and toxicologic data, to improve risk estimates. With this type of combined data, the potential also exists to define exposure levels at which hazard and risk are of minimal concern. Limitations in interpreting biomonitoring data were discussed, including the need for different criteria for applying biomonitoring data for exposure assessment, risk assessment, risk management, or disease prevention purposes. As efforts and resources are expended to improve the ability to apply biomonitoring exposure data in the risk assessment process, it is equally important to communicate the significance of such data to the public.
Key Words: risk assessment—biomonitoring; risk assessment—exposure assessment; risk assessment.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSTRATEGIC BIOMONITORING...CASE STUDY: METHYL EUGENOLDISCUSSIONABOUT HESIREFERENCES |
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On January 16, 2006, the ILSI Health and Environmental Sciences Institute (HESI) held a scientific session on "Integration of Biomonitoring Exposure Data into the Risk Assessment Process" at its annual meeting in Puerto Rico. The session program, organized by the HESI Biomonitoring Technical Committee (an international group of scientists from government, academia, and industry) was designed to share information about global strategic initiatives which collect, refine, apply, and interpret biomonitoring data for various exposure and risk assessment purposes. Presentations were given by scientists from the Centers for Disease Control and Prevention (CDC), the U.S. Environmental Protection Agency (EPA), the National Research Council Committee on Human Biomonitoring for Environmental Toxicants, the German Commission on Human Biomonitoring, and the HESI Biomonitoring Technical Committee. The session closed with a panel discussion.
The purpose of this paper is to briefly present the perspectives offered by the session speakers on diverse, and sometimes overlapping, uses of biomonitoring data, including evaluation of exposure trends, identification of susceptible populations, detection of emerging chemical risks, the conduct of epidemiology studies, and evaluation of risk reduction strategies. While the speakers represent different scientific sectors, they offer strikingly similar views. The authors, experts in their respective fields and institutions, provide a broad yet cohesive discussion of the future of biomonitoring as a mechanism for improving public health.
Biomonitoring is the analytical measurement of biomarkers in specified units of tissues or body products (blood, urine, etc.). Biomarkers are any substances, structures, or processes that are measured to indicate an exposure or susceptibility or that predict the incidence or outcome of disease (Toniolo et al., 1997
). The measurement of biomarkers, in combination with other data, plays an integral role in identifying exposure (sources, trends, etc.), potential human health effects, and/or the effectiveness of public health measures introduced to control exposures. The strategic biomonitoring initiatives discussed in this paper are predominantly focused on characterizing exposures.
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STRATEGIC BIOMONITORING INITIATIVES IN THE UNITED STATES AND EUROPE |
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TOPABSTRACTINTRODUCTIONSTRATEGIC BIOMONITORING...CASE STUDY: METHYL EUGENOLDISCUSSIONABOUT HESIREFERENCES |
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Centers for Disease Control and Prevention
The laboratory at the CDC has provided biomonitoring data for epidemiological studies/investigations and for the National Health and Nutrition Examination Survey (NHANES) for decades. The determination of blood lead concentrations in the general population of the United States has been the signature environmental chemical measurement in NHANES, dating back to NHANES II (1976–1980). These measurements indicated that the mean blood lead levels in the U.S. population declined from 1976 through 1980 from approximately 16 to about 9 µg/dl in parallel with the decrease of lead in gasoline. Interestingly, some models indicated that there would be a lesser decline in blood lead levels as a result of decreased lead in gasoline. These models failed to fully consider the contribution of lead in dust as a major contributor to blood lead levels, used an incorrect air-lead to blood-lead ratio based on subjects exposed to very high lead levels, and incorrectly assumed a linear relationship between high exposures and general population exposures. Blood lead levels have continued to decline in the U.S. population to a geometric mean of less than 2 µg/dl in the 2001–2002 NHANES data. The use of biomonitoring to verify decreased lead exposure is of special importance to the susceptible infant. This decrease is due primarily to mandated actions by government legislation that resulted from human/animal exposure and health effect studies. Other NHANES measurements, such as serum cotinine (a metabolite of nicotine), have verified for all age groups 3 years and older the reduction of exposure to environmental tobacco smoke due to decreased smoking, legislation which bans smoking, and voluntary smoking bans. Another example of the use of biomonitoring is the validation of a reduction in dioxin exposure, primarily due in the United States to EPA regulations on combustion emissions. However, for other environmental chemicals for which complete toxicological and epidemiological databases are not available, it is often necessary to begin compiling data on exposure trends and develop the needed databases while awaiting the results of toxicological tests or epidemiological studies. In this area, the CDC actively acquires exposure data for environmental chemicals and presents the data in a series of reports. The latest report is titled the Third National Report on Human Exposure to Environmental Chemicals (CDC, 2005
). For other chemicals, including the brominated flame retardants (e.g., polybrominated diphenyl ethers), perchlorate, and perfluorinated chemicals (e.g., perfluorooctane sulfonic acid and perfluorooctanoic acid), exposure data have been acquired and are forthcoming. Some of these chemicals, such as the dioxins and perfluorinated compounds, have long biological half-lives, whereas others, such as perchlorate and cotinine, have much shorter biological half-lives. The internal concentrations of long-lived chemicals do not change much over time; however, the internal concentrations of short-lived chemicals can vary a great deal following recent exposures. This factor must be considered when collecting biomonitoring data on an individual. However, for purposes of following trends in a large population (e.g., NHANES), the number of samples analyzed minimizes the effects of individual high and low results. The exposure-effect continuum for environmental chemicals (Fig. 1) is a useful guide for determining associations in epidemiological studies and making risk management and risk assessment decisions. In epidemiological studies, the further along the continuum that exposure can be assessed (optimally, but generally not practically, the biologically effective dose), the more accurately exposure assessment can be related with effect assessment. However, blood levels or urine levels are generally used as a surrogate for the biologically effective dose. In these investigations, the primary emphasis is on providing the correct experimental design to sample at the appropriate times and on determining internal dose levels. The route and pathway of exposure are of lesser concern. If an association is shown, however, the exposure pathway must be fully evaluated for risk management purposes and involves the collection and analysis of environmental media.
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For risk assessment purposes, there is a need for a paradigm shift such that the entire exposure-effect continuum, when possible, is utilized (Fig. 1). Without internal dose information, regulations are promulgated based on levels emitted from a source or presence in environmental media; however, utilizing the entire exposure-effect continuum, coupled with pharmacodynamic and pharmacokinetic data, allows for scientifically derived decision making. Using dioxin as an example, one can work backward from known effects (in animals) to internal dose levels required for these effects and then to exposure levels in the food chain to produce serum levels in humans. Of course, the shift from animal data to human data must be biologically plausible, i.e., the mechanism of action that accounts for the effect in the animal species tested must be present in humans, and any difference in response must be accounted for. Some steps in the exposure-effect continuum are reversible. Even if an internal dose of a chemical can be measured, it will not necessarily lead to a biologically effective dose and result in an effect. It is important to note that internal doses of all chemicals and other substances cannot always be measured.
U.S. Environmental Protection Agency
The U.S. EPA is responsible for developing and implementing regulations that protect public health. Thus, EPA must identify and characterize environmentally related health problems, develop appropriate risk mitigation strategies, and determine if these strategies are effective. In the past, this has been accomplished through environmental monitoring and risk assessments that combine information on the toxicity of a compound with estimates of human exposure. With the explosion in the availability of biomonitoring data, it is important to expand approaches for assessing risks and to use these new data to inform decision making. Ideally, biomonitoring data could be used to evaluate and bound potential health risks. These data could also be combined with other data to identify important routes and pathways of exposure. This information can then be used to target the most effective mitigation strategies. Once regulations are in place, biomonitoring data could be used to understand the impact of these actions on risk reduction (e.g., the use of biomonitoring to verify decreased lead exposure after mandated removal of lead from gasoline).
Detection of a specific biomarker provides information that exposure and absorption has occurred. Often, little else can be concluded regarding when and how the exposure took place. To answer questions about exposure and environmental concentrations that lead to exposures, additional information specific to the exogenous agent (e.g., physical-chemical properties), the exposure pathway (e.g., exposure medium, contact rates), and the biological system (e.g., metabolic pathways) is required. Research at the EPA National Exposure Research Laboratory has focused on developing the information and tools that will allow prediction of exposure based on biomonitoring data. This includes tools and information that will be used for linking biomonitoring data back to environmental concentrations.
Several field-monitoring studies have been conducted in which extensive data were collected on chemical concentrations in environmental and personal exposure samples, along with biomarker measurements. These studies include the National Human Exposure Assessment Survey (NHEXAS) (U.S. EPA, 2006a), the Agricultural Health Study/Pesticide Exposure Study (AHS/PES) (AHS, 2006), and a study of Children's Total Exposure to Persistent Pesticides and Other Persistent Organic Pollutants (CTEPP) (U.S. EPA, 2005; Wilson et al., 2004). Analysis of these data is under way to determine the relationship between the biomarker and the external measurement data, as well as the factors that impact this relationship. Statistical analysis is being conducted using exposure and dose construction, structural equation modeling, and hierarchical Bayesian modeling.
The best case for relating exposure and biomonitoring data is demonstrated in the AHS (2006) in which applicator exposures to pesticides were monitored. An exposure was usually a single event; there was a known period of chemical handling; and multiple urine samples were collected around the event. Urinary excretion rates of 2,4-D showed a pattern consistent with previously reported uptake and elimination rates (Sauerhoff et al., 1977). The relationship between exposure measurements and urine concentrations was statistically significant. In addition, urine concentrations were different across several exposure scenarios (e.g., dermal and inhalation).
The more typical case is seen for CTEPP (U.S. EPA, 2005; Wilson et al., 2004), which was a general population study for young children. The CTEPP study investigated the aggregate exposures of 257 preschool children to chemicals commonly found in their everyday environments (i.e., homes and day care centers). Two chemicals measured at these locations were the pesticide chlorpyrifos and its metabolite trichloropyridinol (TCP). Low exposure levels, multiple exposure routes, and uncertainty about sources and timing of exposures typified CTEPP. Intake or absorbed dose was estimated for both chlorpyrifos and TCP using (1) concentrations measured in environmental and personal samples, (2) questionnaire data on locations and activities that impact exposure, and (3) assumptions about absorption through the lung, skin, and gut. Figure 2 compares intake estimates to the amount of TCP excreted in the urine, showing that more than half of the excreted TCP is not accounted for. Multiple types of analyses have been conducted, all with the same general conclusions: diet predominates predictions of exposure and intake, TCP in the diet is the predominant species, poor correlations (r2 = 0.01) were seen between biomarker and dietary exposures, and the highest correlations were seen between biomarker and air concentrations (r2 = 0.20) (Morgan et al., 2005). The inability to better describe the relationship between exposure and biomarker data could be due to several factors: uncertainty associated with the measurement protocols; algorithms for estimating pathways; and inputs for adsorption, distribution, metabolism, and excretion. Alternatively, exposure pathways can be missing. Hence, different conclusions about exposure levels, routes, and pathways can be drawn depending on the type of uncertainty that predominates. Research is currently under way to reduce the uncertainty associated with the measurement data and the model parameters and structure.
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Exposure and dose models are being developed and linked to guide the collection of biomarkers for future studies, aid in their interpretation, and reconstruct exposure and environmental concentrations from biomarker measurements. The Stochastic Human Exposure and Dose Simulation (SHEDS) model generates route-specific exposure profiles as a function of time (U.S. EPA, 2006b
; Zartarian et al., 2002). The Exposure-Related Dose Evaluation Model (ERDEM) is a physiologically-based pharmacokinetic (PBPK) model that can be used to simulate biomarker concentrations, as well as target dose profiles (U.S. EPA, 2006c). Work is being conducted to develop chemical class-specific PBPK models that can then be used to understand exposure and exposure pathways. Models for trichloroethylene, organophosphate pesticides, and methyl t-butyl ether are being evaluated. Both SHEDS and ERDEM can provide probabilistic simulations for both exposures and biomarker concentrations. The use of population-based models will allow statistical predictions about trends and impacts of mitigation strategies.
European Biomonitoring Initiatives
The use of biomonitoring in environmental medicine in Europe came with the discovery that the general population was exposed to lead at high, and even toxic, levels due to its use in gasoline. This discovery led to the European Commission directive on "Biological Screening of the Population for Lead" (77/312/EEC). Surprisingly, almost 30 years passed before biomonitoring was again considered in Europe. Recently, the member states of the European Union (EU) confirmed their interest in developing a "Coherent Approach to Biomonitoring through the European Environment and Health Action Plan 2004–2010" (EU, 2004).
As a result of this action plan, several activities were undertaken by the EU member states. At a meeting in 2004, participants defined the objectives of further biomonitoring activities: (1) identify policy-relevant objectives, (2) develop protocols, (3) integrate biomonitoring within environmental and health monitoring, and (4) develop communication strategies with stakeholders.
To achieve these objectives, a pilot project on biomonitoring will begin in 2006. It includes the determination of concentrations of lead, methyl mercury, and cotinine in European population groups. Discussion continues on whether to include substances such as phthalates or acrylamide in the study because of their relevance to human health. Furthermore, the inclusion and implementation of biomonitoring into the 7th EU framework program on research is a priority.
On a national level in Germany, the Commission on Human Biomonitoring was established in 1992 at the Federal Agency for the Environment. Since that time, the commission has set reference values for internal exposure of the general population for metals (n = 8) and organic substances (n = 18) (German Human Biomonitoring Commission, 2006). Reference values represent the background exposure of the general population, i.e., the 95th percentile of a parameter in biological material in a representative group of the general population. Moreover, human biomonitoring values (HBM I and HBM II) were established for some metals (n = 3) and for pentachlorophenol. HBM I is the concentration below which there is no risk of adverse health effects. HBM II approximates the no-observed-adverse-effect level based on experience with human exposure and health effects for that substance. If HBM II is exceeded, there is an increased risk of adverse health effects and measures must be taken to reduce the exposure (action level) (Ewers et al., 1999). Reference values in most cases were based on the results of the German Environmental Surveys in which up to 5000 individuals were monitored in three studies between 1985 and 1998 (GerES I-III).
All these and future biomonitoring activities must be based on reliable analytical methods. The Deutsche Forschungsgemeinschaft has supported a program for the establishment of standard operating procedures for biomonitoring since 1975. These methods are tested for reliability and reproducibility. Ten volumes of the "Analyses of Hazardous Substances in Biological Materials" have been published. These documents contain approximately 130 standard operating procedures for the determination of metals, solvents, pesticides, PAHs, aromatic amines, phthalates, acrylamide, etc. (Angerer, 2006; DFG, 2002).
For many years, biomonitoring analyses have included state-of-the-art internal and external quality assessment. Effective external quality assessment schemes for metal analyses have been established in the United States, Canada, and many EU member states. External quality assessment for organic substances is less widespread; however, the German and, to a lesser extent, Finnish schemes offer several organic parameters such as solvents, their metabolites, organochlorine compounds, pesticides, fluorinated compounds, phthalates, etc. (Schaller, 2002).
From an occupational medicine perspective, the EU enacted a dozen directives between 1980 and 2004 on chemical substances. In most of these directives, however, biomonitoring is mentioned without binding obligations. In only one of these directives was a limit value established (i.e., for lead in 1982). Twenty years later, the EU Scientific Committee on Occupational Exposure Limits initiated activities on biomonitoring and established a new Biological Limit Value for lead.
Only in Germany is biomonitoring mandatory in workplaces by national legislation. Through the experience in Germany, biomonitoring tools such as methods, quality assessment, reference and limit values have been generated. Given these developments, biomonitoring can be applied in both occupational and environmental medicine in the future.
National Research Council Committee on Human Biomonitoring of Environmental Toxicants
Biomonitoring has the potential to revolutionize environmental health research and practice. The release of the Third National Report on Human Exposure to Environmental Chemicals by CDC marked a giant step forward in understanding the relationship between exposure to chemicals and their potential health effects. The release of the Third National Report also led to nationwide headlines that demonstrated the difficulty of interpreting the results of biomonitoring. For example, some headlines heralded the dramatic drop in blood lead levels of the population. In contrast, other headlines warned that the population is full of contaminants and awash in pesticide solvents and metals. Clearly, measuring chemicals in the human body is easier than interpreting the public health implications of their presence.
The interpretation and communication of the results of biomonitoring studies presents an enormous challenge. Addressing this challenge is essential to moving biomonitoring science and applications forward. Recognizing this, the U.S. Congress directed EPA to request a National Research Council (NRC) study of biomonitoring for toxicants. In 2004, the NRC established the Committee on Human Biomonitoring for Environmental Toxicants (NRC, 2004). The Committee was tasked with a broad charge: review current practices; recommend ways to improve the interpretation and uses of biomonitoring data; develop a research agenda for improving the characterization of health risks; and improve the use of biomonitoring to monitor changes relevant to public health and environmental policies.
The NRC Committee was selected to represent the multidisciplinary nature of biomonitoring, and includes broad expertise in toxicology, epidemiology, risk assessment and communication, analytical chemistry, medicine, occupational health, and children's health. To assure representation of perspectives from outside the United States, the Committee included a number of international scientists. The Committee held workshops and conducted a broad review of the literature on the state of the science of biomonitoring. The Committee also heard from a broad range of scientists and practitioners involved in biomonitoring. At the workshops, industry scientists, academic researchers, federal public health and environmental officials, and state agency scientists presented their work and recommendations.
Recognizing that there are already a number of ethical concerns regarding biomonitoring research and applications, the NRC Committee also held a session on bioethics in biomonitoring. In this session, the challenge of anonymous sampling, reporting, and interpretation of results in the absence of scientific certainty regarding public health implications were examined, and issues concerning informed consent from biomonitoring study participants were discussed. In particular, the Committee examined current practices of biomonitoring research involving children.
In conducting the study, the NRC Committee recognized that there are many applications of biomonitoring data. Results provide a measure of the amount of a chemical absorbed into the body. As the CDC Third National Report demonstrates, biomonitoring data can provide measures of individual or population exposure levels. Although there are many limitations to the current science, biomonitoring can also be used to evaluate health effects and identify those at highest risk. From a public health policy perspective, biomonitoring can provide a way to track population exposure trends and guide prevention strategies.
The NRC Committee carefully reviewed the limitations of the current science. At the present time, there are tremendous gaps in our understanding of the public health implications of the presence of environmental toxicants in the human body. For example, although an ever-increasing number of chemicals can be measured in the human body, only a small percentage of these chemicals have recognized health benchmarks. As a result, the ability to communicate the risks associated with biomonitoring results is limited. The Committee examined these gaps and research needs in toxicology, pharmacokinetics, epidemiology, and communication. The Committee also examined a number of historical and contemporary case studies to understand applications, limitations, and needs in biomonitoring.
Scheduled for release in mid-2006, the report of the NRC Committee on Human Biomonitoring for Environmental Toxicants is expected to provide a framework for future biomonitoring surveillance and research, catalyze multidisciplinary research, and serve as a resource for investigators and decision makers alike.
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CASE STUDY: METHYL EUGENOL |
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TOPABSTRACTINTRODUCTIONSTRATEGIC BIOMONITORING...CASE STUDY: METHYL EUGENOLDISCUSSIONABOUT HESIREFERENCES |
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The availability of biomonitoring, toxicology, and pharmacokinetics data on methyl eugenol offers an opportunity to examine how biomonitoring data can be integrated into the exposure-effect continuum ECETOC, 2005; Robison and Barr, 2006 (Fig. 1). To illustrate this integration, methyl eugenol was presented as a case study at the January 2006 HESI scientific session on biomonitoring. Methyl eugenol is a member of a structural family of allylalkoxy benzene derivatives that are naturally occurring compounds found in a variety of food sources, including spices, plant-derived oils, and nutritionally important foods such as bananas and oranges (Smith et al., 2002
). Given the natural occurrence of methyl eugenol in food sources, a majority of the population is likely to be exposed by virtue of dietary consumption.
For the purposes of exposure assessment, the parent compound, methyl eugenol, was used as the biomarker of exposure. The metabolites of methyl eugenol have been described and, at typical dietary exposures, O-demethylation is the primary metabolic pathway (NTP, 2000; Smith et al., 2002). However, there are other known and predicted metabolites that are potentially more closely linked to a biomarker of effect. The 1'-hydroxymethyl eugenol metabolite is hypothesized to be the critical reactive metabolite which could form DNA adducts. Recently, mechanistic evidence suggesting that a 1'-hydroxymethyl eugenol metabolite is involved in DNA adduct formation has been reviewed (Rietjens et al., 2005). In addition, it has been shown that human cytochrome P450s 1A2, 2C9, and 2C19 can form the 1'-hydroxymethyl eugenol metabolite in vitro (Jeurissen et al., 2006).
The analytical method to detect methyl eugenol in human blood samples is well characterized (Barr et al., 2000). Biomonitoring data indicate that blood levels may range from less than about 3 pg to almost 400 pg methyl eugenol/g of serum. (Using common physiological values, this translates to about 3–12 µg methyl eugenol/kg/day.) Limited data in humans indicate that methyl eugenol is relatively short-lived in the body (Schecter et al., 2004). A small group of fasted healthy volunteers ingested ginger-snap cookies containing methyl eugenol; data from this study indicate that it is cleared from the body relatively quickly. The serum levels obtained in the study translate to an exposure of about 4 µg methyl eugenol/kg/day (Schecter et al., 2004). This value is comparable to previous estimates via the diet (about 5 µg/kg/day) (Smith et al., 2002), and is consistent with biomonitoring data obtained for methyl eugenol (Barr et al., 2000). Importantly, the methyl eugenol levels obtained in the biomonitoring studies are single point samples which do not account for day-to-day variation in diet or intermittent sources of exposure. In light of this, it is interesting to note that even though there are a variety of potential dietary and environmental sources of exposure, human blood levels are, in general, relatively low.
Methyl eugenol and the other allylalkoxybenzene derivatives are generally considered to be nonmutagenic or nonclastogenic at biologically relevant doses (i.e., typical dietary concentrations); however, both methyl eugenol and estragole at higher concentrations have been shown to induce unscheduled DNA synthesis in vitro (Howes et al., 1990; NTP, 2000). Toxicology studies in animals have shown that lifetime, relatively high-bolus doses administered orally result in hepatic neoplasms in rats and mice. Importantly, there is little or no information on the potential impact of chronic low-level exposure in rodents or humans. There has been the suggestion that administration of relatively high doses overwhelms the most common metabolic pathways, resulting in the formation of a reactive carbonium ion from the 1'-hydroxymethyl eugenol metabolite (Smith et al., 2002; Rietjens et al., 2005). Furthermore, an understanding is lacking regarding how the effects observed at high-bolus doses relate to the exposures that result when food containing relatively modest levels of methyl eugenol is consumed. Recently, it has been reported that cytochrome P450 1A2 is primarily responsible for the metabolism of methyl eugenol but, at higher concentrations, P450 2C9 and 2C19 also contribute to the metabolism (Jeurissen et al., 2006). This may help explain the differences observed at low versus high concentrations of methyl eugenol. Another consideration is how structurally-related compounds such as estragole that are also found in the diet impact the metabolism and toxicity of methyl eugenol. Overall, the level of methyl eugenol detected in biomonitoring studies indicates that human exposure is several orders of magnitude lower than the lowest dose used in the rodent bioassay. There are no human epidemiology studies that examine the relationship between typical dietary exposure to methyl eugenol and potential health effects.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSTRATEGIC BIOMONITORING...CASE STUDY: METHYL EUGENOLDISCUSSIONABOUT HESIREFERENCES |
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During the January 2006 HESI biomonitoring session, speakers participated in a panel discussion to respond to questions and present perspectives regarding the potential for biomonitoring to improve the science of risk assessment. Issues discussed included the uses, limitations, and communication of biomonitoring data. For example, as CDC and others provide better estimates of biological concentrations of chemicals and metals in populations, these data can be combined with other exposure indices and epidemiological and toxicology data to improve risk estimates and define lower limits of exposure at which hazard and risk are of minimal concern. Scientific limitations in interpreting biomonitoring data are numerous but not insurmountable: (1) such data often represent only a single point in time for an individual; (2) there is an inability to link to exposure history, lifestyle or other influential factors; and (3) the sampling approach may provide only limited insight into susceptible populations.
A concern which is raised frequently among the public and the environmental health community is the misinterpretation of biomonitoring data. While panelists agreed that appropriate cautionary statements are necessary to ensure that biomonitoring data are not misused or over-interpreted in a risk assessment context, the experts noted that there are no hard and fast rules for applying biomonitoring data for exposure assessment, risk assessment, risk management, or disease prevention purposes. Each one of these uses requires different criteria for applying and interpreting biomonitoring information. For instance, epidemiology/human effects data would not be needed to address the question of whether there is a trend for a substance or an increase (or decrease) in concentrations found in the environment over time; however, epidemiology/human effects data (and or animal toxicology data) would be necessary if the question being asked is whether there is a potential human health risk from exposure to the substance. The risk assessor/risk manager will utilize different data and criteria depending on the question. The need for an integrated series of interpretive steps to ensure the incorporation of data relevant to the specific question being addressed is generally recognized. Development of a process to ensure that such steps are included in addressing specific biomonitoring questions is the subject of discussion by the HESI Biomonitoring Technical Committee.
Speakers and participants in the HESI session identified future challenges for biomonitoring. The role of "natural" chemicals (e.g., phytoestrogens, glycoalkaloids, and others) will be particularly important for understanding source information and changes in human biomonitoring levels. Aggregate exposures and cumulative risk are critical concerns for populations and individuals. The study of intra- and interindividual variability will help elucidate differences in biomonitoring measurements in heterogeneous populations.
Finally, several speakers addressed public misunderstanding about the relationship between the presence of contaminants in human tissues and the occurrence of human health effects. While speakers agreed that a link can be made between presence and effect only with support from scientific data, they acknowledged that the general public perceives that no level of contaminant in the human body is acceptable. Thus, as efforts and resources are expended to improve the ability to apply biomonitoring exposure data in the risk assessment process, it is equally important to communicate the significance of such data to the public.
A number of scientific issues need to be resolved before biomonitoring can be fully integrated into existing exposure and risk assessment practices. However, even in the absence of resolution, biomonitoring data can still inform weight-of-evidence discussions and help set priorities for further research efforts. These questions and challenges will form the basis of future work by the HESI Biomonitoring Technical Committee as it continues to explore the use of biomonitoring data for exposure and risk assessment purposes.
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ABOUT HESI |
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TOPABSTRACTINTRODUCTIONSTRATEGIC BIOMONITORING...CASE STUDY: METHYL EUGENOLDISCUSSIONABOUT HESIREFERENCES |
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The ILSI Health and Environmental Sciences Institute (HESI) is a global branch of the International Life Sciences Institute, a public, nonprofit scientific foundation with branches throughout the world. HESI provides an international forum to advance the understanding and application of scientific issues related to human health, toxicology, risk assessment and the environment. HESI is widely recognized among scientists from government, industry and academia as an objective, science-based organization within which important issues of mutual concern can be discussed and resolved in the interest of improving public health. As part of its public benefit mandate, HESI's activities are carried out in the public domain, generating data and other information for broad scientific use and application.
The mission of the HESI Technical Committee on Integration of Biomonitoring Exposure Data into the Risk Assessment Process (the Biomonitoring Technical Committee) is twofold: (1) to delineate the appropriate scientific use(s) of biomonitoring tools and/or biomonitoring data needed to characterize exposure to chemicals and (2) to define the criteria needed for integration of biomonitoring and toxicology data into a robust risk assessment process.
Further information about HESI can be found at http://www.hesiglobal.org.
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NOTES |
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Disclaimer: The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the federal agencies or other institutions represented by the authors.
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ACKNOWLEDGMENTS |
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The authors extend their appreciation to Prof. Alan R. Boobis (Imperial College London) for reviewing the manuscript as part of the HESI peer review process prior to its submission for publication.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSTRATEGIC BIOMONITORING...CASE STUDY: METHYL EUGENOLDISCUSSIONABOUT HESIREFERENCES |
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Agricultural Health Study (AHS) (2006). Agricultural Health Study. National Institutes of Health (National Cancer Institute and National Institute of Environmental Health Sciences) and the U.S. Environmental Protection Agency. Available: http://www.aghealth.org/.
Angerer, J. (2006). The MAK-Collection for Occupational Health and Safety. Part IV: Biomonitoring Methods, Vol. 10. Wiley-VCH, Weinheim, Germany.
Barr, D. B., Barr, J. R., Bailey, S. L., Lapeza, C. R., Jr, Beeson, M. D., Caudill, S. P., Maggio, V. L., Schecter, A., Masten, S. A., Lucier, G. W., et al. (2000). Levels of methyl eugenol in a subset of adults in the general U.S. population as determined by high resolution mass spectrometry. Environ. Health Perspect. 108, 323–328.
Centers for Disease Control and Prevention (CDC) (2005). Third National Report on Human Exposure to Environmental Chemicals. Atlanta, GA. Available: www.cdc.gov/exposurereport.
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