Using Biomonitoring Equivalents to Interpret Human Biomonitoring Data in a Public Health Risk Context

Summit Toxicology, LLP, 165 Valley Road, Lyons, CO 80540, USA.
Journal of Applied Toxicology (Impact Factor: 2.98). 05/2009; 29(4):275-88. DOI: 10.1002/jat.1410
Source: PubMed


Increasingly sensitive analytical tools allow measurement of trace concentrations of chemicals in human biological media in persons from the general population. Such data are being generated by biomonitoring programs conducted by the US Centers for Disease Control and other researchers. However, few screening tools are available for interpretation of such data in a health risk assessment context. This review describes the concept and implementation of Biomonitoring Equivalents (BEs), estimates of the concentration of a chemical or metabolite in a biological medium that is consistent with an existing exposure guidance value such as a tolerable daily intake or reference dose. The BE approach integrates available pharmacokinetic data to convert an existing exposure guidance value into an equivalent concentration in a biological medium. Key concepts regarding the derivation and communication of BE values resulting from an expert workshop held in 2007 are summarized. BE derivations for four case study chemicals (toluene, 2,4-dichlorophenoxyacetic acid, cadmium and acrylamide) are presented, and the interpretation of biomonitoring data for these chemicals is presented using the BE values. These case studies demonstrate that a range of pharmacokinetic data and approaches can be used to derive BE values; fully developed physiologically based pharmacokinetic models, while useful, are not required. The resulting screening level evaluation can be used to classify these compounds into relative categories of low, medium and high priority for risk assessment follow-up. Future challenges related to the derivation and use of BE values as tools in risk management are discussed.

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Available from: Sean M Hays
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    • "At present, human exposure assessment is based largely on measured levels of environmental agents in the human environment (U.S. EPA 2010); in some cases, internal dose measures may also be obtained using biomonitoring (Hays and Aylward 2008) or pharmacokinetic modeling (Barton et al. 2007). In the NexGen approach, exposure assessment will focus more on direct measures of critical toxicity pathway perturbations in humans using advanced biomonitoring techniques (NRC 2012) coupled with innovative new high throughput approaches to obtaining indicators of exposure to large numbers of environmental agents simultaneously (Jones et al. 2012). "
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    ABSTRACT: In 2011, the U.S. Environmental Protection Agency initiated the NexGen project to develop a new paradigm for the next generation of risk science. The NexGen framework was built on three cornerstones: the availability of new data on toxicity pathways made possible by fundamental advances in basic biology and toxicological science; the incorporation of a population health perspective that recognizes that most adverse health outcomes involve multiple determinants; and a renewed focus on new risk assessment methodologies designed to better inform risk management decision making. The NexGen framework has three phases. Phase I (objectives) focuses on problem formulation and scoping, taking into account the risk context and the range of available risk management decision making options. Phase II (risk assessment) seeks to identify critical toxicity pathway perturbations using new toxicity testing tools and technologies, and to better characterize risks and uncertainties using advanced risk assessment methodologies. A blueprint for pathway-based toxicity testing was provided by the 2007 U.S. National Research Council (NRC) report, Toxicity Testing in the 21st Century: A Vision and a Strategy; guidance on new risk assessment methods is provided by the 2009 NRC report, Science and Decisions, Advancing Risk Assessment. Phase III (risk management) involves the development of evidence-based population health risk management strategies of a regulatory, economic, advisory, community-based, or technological nature, using sound principles of risk management decision making. Analysis of a series of case-study prototypes indicated that many aspects of the NexGen framework are already beginning to be adopted in practice.
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    • "The BE is defined as the concentration of a chemical or metabolite in a biological medium (blood, urine, human milk, etc.) that is consistent with an existing exposure guidance value such as a tolerable daily intake (TDI) or reference dose (RfD). Subsequently, the BE approach has been extensively refined and expanded (reviewed in Becker et al., 2012; Hays & Aylward, 2009), and BE values have been derived for approximately 80 chemicals, including persistent organic compounds (e.g. dioxins, hexachlorobenzene, and DDT), approximately 40 volatile organic compounds, phthalates and phenols (bisphenol A, triclosan and several phthalates), certain pyrethroid pesticides, and for selected brominated flame retardant compounds (Angerer et al., 2011).Scientists from the private sector, CDC/ATSDR and US EPA have recently collaborated to compare BEs to measured biomarker concentrations for approximately 130 substances in the CDC’s National Exposure Report to provide a risk assessment perspective on the significance of the levels of these substances found in the US population (Aylward et al., 2013). "
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    ABSTRACT: Abstract Over the last dozen years, many national and international expert groups have considered specific improvements to risk assessment. Many of their stated recommendations are mutually supportive, but others appear conflicting, at least in an initial assessment. This review identifies areas of consensus and difference and recommends a practical, biology-centric course forward, which includes: (1) incorporating a clear problem formulation at the outset of the assessment with a level of complexity that is appropriate for informing the relevant risk management decision; (2) using toxicokinetics and toxicodynamic information to develop Chemical Specific Adjustment Factors (CSAF); (3) using mode of action (MOA) information and an understanding of the relevant biology as the key, central organizing principle for the risk assessment; (4) integrating MOA information into dose-response assessments using existing guidelines for non-cancer and cancer assessments; (5) using a tiered, iterative approach developed by the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) as a scientifically robust, fit-for-purpose approach for risk assessment of combined exposures (chemical mixtures); and (6) applying all of this knowledge to enable interpretation of human biomonitoring data in a risk context. While scientifically based defaults will remain important and useful when data on CSAF or MOA to refine an assessment are absent or insufficient, assessments should always strive to use these data. The use of available 21st century knowledge of biological processes, clinical findings, chemical interactions, and dose-response at the molecular, cellular, organ and organism levels will minimize the need for extrapolation and reliance on default approaches.
    Full-text · Article · Jul 2013 · Critical Reviews in Toxicology
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    • "The report by the National Research Council ''Toxicity Testing in the 21st Century'' (NRC, 2007) has spawned multiple research efforts in the United States and Europe aimed toward use of in vitro HTS assays in the toxicological assessment of environmental chemicals (Abbott, 2009; Kavlock et al., 2009; Knight, 2008). However, meaningful incorporation of these in vitro findings into such an assessment is dependent upon adequate consideration of in vivo pharmacokinetics to determine the relevance of these data to the external and internal doses achieved during human exposure scenarios (Blaauboer, 2010; Hays and Aylward, 2009). Within the pharmaceutical industry, IVIVE modeling approaches have been widely used to assess the preclinical pharmacokinetics of candidate molecules (Caldwell et al., 2009; De Buck and Mackie, 2007). "
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    ABSTRACT: High-throughput in vitro toxicity screening can provide an efficient way to identify potential biological targets for chemicals. However, relying on nominal assay concentrations may misrepresent potential in vivo effects of these chemicals due to differences in bioavailability, clearance, and exposure. Hepatic metabolic clearance and plasma protein binding were experimentally measured for 239 ToxCast Phase I chemicals. The experimental data were used in a population-based in vitro-to-in vivo extrapolation model to estimate the daily human oral dose, called the oral equivalent dose, necessary to produce steady-state in vivo blood concentrations equivalent to in vitro AC(50) (concentration at 50% of maximum activity) or lowest effective concentration values across more than 500 in vitro assays. The estimated steady-state oral equivalent doses associated with the in vitro assays were compared with chronic aggregate human oral exposure estimates to assess whether in vitro bioactivity would be expected at the dose-equivalent level of human exposure. A total of 18 (9.9%) chemicals for which human oral exposure estimates were available had oral equivalent doses at levels equal to or less than the highest estimated U.S. population exposures. Ranking the chemicals by nominal assay concentrations would have resulted in different chemicals being prioritized. The in vitro assay endpoints with oral equivalent doses lower than the human exposure estimates included cell growth kinetics, cytokine and cytochrome P450 expression, and cytochrome P450 inhibition. The incorporation of dosimetry and exposure provide necessary context for interpretation of in vitro toxicity screening data and are important considerations in determining chemical testing priorities.
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