Article

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: 3.17). 05/2009; 29(4):275-88. DOI: 10.1002/jat.1410
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Sean M Hays, Jun 30, 2015
1 Follower
 · 
100 Views
  • Source
    [Show abstract] [Hide abstract]
    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.
    Environmental Health Perspectives 04/2014; 122(8). DOI:10.1289/ehp.1307260 · 7.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Toxicological Sciences 09/2011; 125(1):157-74. DOI:10.1093/toxsci/kfr254 · 4.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This thesis presents a series of investigations into the biokinetic behavior of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds and the application of biokinetic modeling and biomonitoring data in quantitative risk assessment for these compounds. The biokinetic properties of TCDD and related compounds affect nearly every facet of the typical risk assessment procedure as applied to these compounds. Qualitative and quantitative differences in the distribution and elimination of TCDD exist between high and low doses, between species, and even between bolus vs. subchronic dosing administration regimens; similarly, differences exist between TCDD and other dioxin, furan, and PCB compounds of interest. These factors should be considered in risk assessments for dioxins. Because of these complexities, preference should be given to studies most easily interpretable in the context of current human exposure tracking and assessment, which is dominated by the use of biomonitoring efforts. Where possible, use of human studies that rely upon biomonitoring data for exposure quantification concurrent with the measurement of outcome of interest may provide the most reliable basis for risk assessment. Where such data are judged to be unavailable or insufficient, animal studies conducted under chronic or subchronic dosing regimens with measured tissue concentrations may provide the most relevant dose-response data. The substantial uncertainties and interindividual variability in human biokinetics suggests that exposure-response assessments relying on extensive back-calculation of serum TCDD levels should be used only with a great deal of caution, perhaps as supportive analyses rather than the main basis for quantitative risk assessment. Research presented here uses newly-available data sets on elimination of TCDD in highly-exposed human populations to modify and implement a previously-developed model of distribution and elimination for TCDD and to examine the sources of variability and uncertainty involved in the application of such modeling to human occupational cohorts. This research demonstrates that the resulting uncertainty and variations in estimated cumulative exposures may substantially impact a quantitative risk assessment derived based on such estimated exposures. Other research presented in this dissertation demonstrates a variety of approaches for using human biomonitoring and response data in risk assessment for cancer and non-cancer endpoints. Finally, remaining issues related to the role of biokinetics in interspecies extrapolation and risk assessment for dioxins and related compounds are identified. These include the need for assessment of relative potencies on a tissue concentration (rather than intake) basis and the need for further understanding of the role of lactational transfer and interspecies correspondence in critical developmental windows in the occurrence of developmental effects of dioxin-like compounds.