Addressing human variability in next-generation human health risk assessments of environmental chemicals Lauren Zeise, Frédéric Y. Bois, Weihsueh A. Chiu, Dale B. Hattis, Ivan Rusyn, Kathryn Z. Guyton To cite this version: Lauren Zeise, Frédéric Y. Bois, Weihsueh A. Chiu, Dale B. Hattis, Ivan Rusyn, et al.. Addressing human variability in next-generation human health risk assessments of environmental chemicals. En- vironmental Health Perspectives, National Institute of Environmental Health Sciences, 2013, 121 (1), pp.23-31. 10.1289/ehp.1205687. ineris-00961796 HAL Id: ineris-00961796 https://hal-ineris.archives-ouvertes.fr/ineris-00961796 Submitted on 20 Mar 2014 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Review Addressing Human Variability in Next-Generation Human Health Risk Assessments of Environmental Chemicals Lauren Zeise,1 Frederic Y. Bois,2 Weihsueh A. Chiu,3 Dale Hattis,4 Ivan Rusyn,5 and Kathryn Z. Guyton3 1Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, California, USA; 2Institut National de l’Environnement Industriel et des Risques (INERIS), Verneuil en Halatte, France; 3National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC, USA; 4George Perkins Marsh Institute, Clark University, Worcester, Massachusetts, USA; 5Department of Environmental Sciences and Engineering, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina, USA In this review, we explore how next­ Background: Characterizing variability in the extent and nature of responses to environmental generation (“NexGen”) human health risk exposures is a critical aspect of human health risk assessment. assessments of chemi cals might take advantage Objective: Our goal was to explore how next-generation human health risk assessments may of novel data to better characterize and quan­ better characterize variability in the context of the conceptual framework for the source-to-outcome tify variability in susceptibility, by using and continuum. expanding upon current analytical methods. Methods: This review was informed by a National Research Council workshop titled “Biological We begin by describing biological variabil­ Factors that Underlie Individual Susceptibility to Environmental Stressors and Their Implications ity through the conceptual framework of the for Decision-Making.” We considered current experimental and in silico approaches, and emerg- source­to­outcome continuum. Next, the util­ ing data streams (such as genetically defined human cells lines, genetically diverse rodent models, human omic profiling, and genome-wide association studies) that are providing new types of infor- ity of that framework is illustrated in a review mation and models relevant for assessing interindividual variability for application to human health of current approaches to describing variability risk assessments of environ mental chemi cals. in susceptibility in human health risk assess­ ments. Then, emerging data streams that may DISCUSSION : One challenge for characterizing variability is the wide range of sources of inherent biological variability (e.g., genetic and epigenetic variants) among individuals. A second challenge is be informative in characterizing human vari­ that each particular pair of health outcomes and chemi cal exposures involves combinations of these ability in susceptibility are described. Finally, sources, which may be further compounded by extrinsic factors (e.g., diet, psychosocial stressors, we consider the opportunities, challenges other exogenous chemi cal exposures). A third challenge is that different decision contexts present and methods for using emerging data to help distinct needs regarding the identification—and extent of characterization—of inter individual varia- assess inter individual variability in responses bility in the human population. to environmental chemicals across different Conclusions: Despite these inherent challenges, opportunities exist to incorporate evidence from decision contexts. emerging data streams for addressing inter individual variability in a range of decision-making contexts. Susceptibility as a Function Key words: environ mental agents, genetics, human health risk assessment, modeling, omics tech- of the Source-to-Outcome nologies, susceptible populations, variability. Environ Health Perspect 121:23–31 (2013). http:// dx.doi.org/10.1289/ehp.1205687 [Online 19 October 2012] Continuum and Biological Variability The “source­to­outcome continuum” [U.S. Human variability underlies differences in the authority; the available time, resources, and Environmental Protection Agency (EPA) degrees and ways in which people respond expertise to collect data and conduct analyses; 2007; NRC 2007] is a conceptual frame­ to environ mental chemi cals, and address­ and stakeholder concerns. work for human health risk assessment of ing these differences is a key consideration Over the past decade, efforts to systemati­ environ mental chemi cals in which changes in in human health risk assessments for chemi­ cally “map” human variability have expanded the sources of chemi cals in the environment cals [Guyton et al. 2009; Hattis et al. 2002; dramatically, focusing mainly on genetic National Research Council (NRC) 2009]. variation (Schadt and Björkegren 2012). In Address correspondence to L. Zeise, California A large array of possible health outcomes is addition to genetic differences, omics stud­ Environmental Protection Agency, 1515 Clay St., of concern for such assessments, and many ies have examined the impact of epigenetic, 16th Floor, Oakland, CA 94612 USA. Telephone: sources of variation can influence the sever­ transcriptomic, proteomic, and metabolo­ (510) 622­3195. Fax: (510) 622­3211. E­mail: ity and frequency of the adverse effects at dif­ mic variation on disease susceptibility, [email protected] This review was informed by the discussions and ferent exposure levels. These sources may be prognosis, or options for pharmacotherapy presentations at a National Research Council (NRC) intrinsic (e.g., heritable traits, life stage, aging), (Chen et al. 2008; Emilsson et al. 2008; Illig workshop titled “Biological Factors that Underlie or extrinsic, exogenous, and acquired (e.g., et al. 2010; Manolio 2010; Schadt 2009). Individual Susceptibility to Environmental Stressors background health conditions, co­occurring Tailored chemotherapy treatment based on and Their Implications for Decision­Making” held in chemi cal exposures, food and nutrition status, patient (Phillips and Mallal 2010) or tumor April 2012 in Washington, DC. psychosocial stressors). Interactions between (La Thangue and Kerr 2011) genetics is an We thank the staff, particularly K. Sawyer and M. Shelton­Davenport, and members of the NRC’s inherent and extrinsic factors create the large example of a significant success in applying Committee on Emerging Science for Environmental range of biological variation exhibited in such discoveries; however, for many diseases, Health Decisions. We also thank I. Cote for her response to a chemi cal exposure (NRC 2009). the substantial nongenetic variation in disease thoughtful comments. Given that biological variability in susceptibil­ or treatment outcomes has limited their util­ The views in this article are those of the authors, ity is context­ dependent, so too is the extent to ity. Thus, the characterization of the broad and do not necessarily reflect the views or policies which it needs to be described and quantified set of environ mental factors, including those of the U.S. Environmental Protection Agency or the California Office of Environmental Health Hazard to inform any particular environ mental deci­ related to chemical exposures, that may con­ Assessment. sion. The salience of variability information for tribute to disease is directly relevant to both The authors declare they have no actual or potential specific choices is affected by the range of avail­ personal ized medicine and environ mental competing financial interests. able risk management options; the regulatory health protection (Khoury et al. 2011). Received 28 June 2012; accepted 19 October 2012. Environmental Health Perspectives • VOLUME 121 | NUMBER 1 | January 2013 23 Zeise et al. are further propagated within the individual • Internal doses are the amounts/concentrations altered by interactions with environ mental through a series of biological and physiologi­ of environmental chemicals or their metabo­ chemi cals or their metabolites, and are related cal steps that may ultimately manifest as an lites at the target site(s) of interaction with to internal doses by pharmaco dynamic (PD) adverse health outcome (Figure 1): biological molecules, and are related to exter­ processes. Variation leading to differential • Source/media concentrations are measures nal doses by pharmaco kinetic (PK) processes. susceptibility can stem from differences in of the chemi cal, which may change under Susceptibility may arise from differences in transport