Population Effects and Variability

Abstract

Chemical risk assessment for human health requires a multidisciplinary approach through four steps: hazard identification and characterization, exposure assessment, and risk characterization. Hazard identification and characterization aim to identify the metabolism and elimination of the chemical (toxicokinetics) and the toxicological dose-response (toxicodynamics) and to derive a health-based guidance value for safe levels of exposure. Exposure assessment estimates human exposure as the product of the amount of the chemical in the matrix consumed and the consumption itself. Finally, risk characterization evaluates the risk of the exposure to human health by comparing the latter to with the health-based guidance value. Recently, many research efforts in computational toxicology have been put together to characterize population variability and uncertainty in each of the steps of risk assessment to move towards more quantitative and transparent risk assessment. This chapter focuses specifically on modeling population variability and effects for each step of risk assessment in order to provide an overview of the statistical and computational tools available to toxicologists and risk assessors. Three examples are given to illustrate the applicability of those tools: derivation of pathway-related uncertainty factors based on population variability, exposure to dioxins, dose-response modeling of cadmium.

Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse

“…There is a crucial need for the development of approaches to estimate the quantitative impact of human interindividual variability in personal risk from chemical exposures (Zeise et al 2013), and with adequate human data, a number of statistical and computational tools are available to toxicologists and risk assessors (Dorne et al 2012). …”

Human Biomonitoring in the Oil Shale Industry Area in Estonia—Overview of Earlier Programmes and Future Perspectives

“…However, effect biomarkers have been found to be effective only when people exposed to high levels of contaminants (e.g., working with mutagenic agents), and they are difficult to use to differentiate the effects of individuals. Toxicological studies have shown that individuals' responses to chemical exposure can often vary significantly (15). Ladeira and Viegas (14) consider that such differences between individuals may be genetically mediated or caused by some environmental stressor, disease process, or other epigenetic factor.…”

Modern methodologies and tools for human hazard assessment of chemicals

“…The US-EPA has discussed a number of criteria for the acceptance of PB-TK models in risk assessment: (1) the model represents the species and life stage of relevance for the specific risk assessment, (2) the model has been evaluated and peer-reviewed for transparency, adequacy of its structure and parameters, and (3) the model provides adequate simulations of the concentration of the toxic moiety (parent compound or metabolite(s)) in the target organ (or a surrogate compartment of the body), relevant exposure route(s) and relevant time-course for which the chemical would be present in that target organ/surrogate compartment (US-EPA, 2006). In the future, PB-TK models may be increasingly used, on a case by case basis depending on the purpose of the risk assessment and data availability, as more generic predictive tools become available (Conolly et al, 2005;US-EPA, 2007;EFSA, 2008;Dorne et al, 2012). In the future, PB-TK models may be increasingly used, on a case by case basis depending on the purpose of the risk assessment and data availability, as more generic predictive tools become available (Conolly et al, 2005;US-EPA, 2007;EFSA, 2008;Dorne et al, 2012).…”

“…In terms of validation, 4 key aspects to be reviewed have been identified 1. model purpose and structure, 2. mathematical representation, 3. calibration of the parameter estimations, and 4. computer implementation of the model. In the future, PB-TK models may be increasingly used, on a case by case basis depending on the purpose of the risk assessment and data availability, as more generic predictive tools become available (Conolly et al, 2005;US-EPA, 2007;EFSA, 2008;Dorne et al, 2012).…”