Use In Human Health Risk Assessment Research Articles

Availability, Quality, and Relevance of Toxicogenomics Data for Human Health Risk Assessment: A Scoping Review of the Literature on Trihalomethanes.

Human health risk assessment (HHRA) must be adapted to the challenges of the 21st century, and the use of toxicogenomics data in HHRA is among the changes that regulatory agencies worldwide are trying to implement. However, the use of toxicogenomics data in HHRA is still limited. The purpose of this study was to explore the availability, quality, and relevance to HHRA of toxicogenomics publications as potential barriers to their use in HHRA. We conducted a scoping review of available toxicogenomics literature, using trihalomethanes as a case study. Four bibliographic databases (including the Comparative Toxicogenomics Database) were assessed. An evaluation table was developed to characterize quality and relevance of studies included on the basis of criteria proposed in the literature. Studies were selected and analyzed by 2 independent reviewers. Only 9 studies, published between 1997 and 2015, were included in the analysis. Based on the selected criteria, critical methodological details were often missing; in fact, only 3 out of 9 studies were considered to be of adequate quality for HHRA. No studies met >3 (out of 7) criteria of relevance to HHRA (eg, adequate number of doses and sample size). This first scoping review of toxicogenomics publications on trihalomethanes shows that low availability, quality, and relevance to HHRA of toxicogenomics publications presents potential barriers to their use in HHRA. Improved reporting of methodological details and study design is needed in the future so that toxicogenomics studies can be appropriately assessed regarding their quality and value for HHRA.

Leveraging human genetic and adverse outcome pathway (AOP) data to inform susceptibility in human health risk assessment

Estimation of susceptibility differences in human health risk assessment (HHRA) has been challenged by a lack of available susceptibility and variability data after exposure to a specific environmental chemical or pharmaceutical. With the increasingly large number of available data sources that contain polymorphism and other genetic data, human genetic variability that informs susceptibility can be better incorporated into HHRA. A recent policy, the 2016 The Frank R. Lautenberg Chemical Safety for the twenty-first Century Act, requires the US Environmental Protection Agency to evaluate new and existing toxic chemicals with explicit consideration of susceptible populations of all types (life stage, exposure, genetic, etc.). We propose using the adverse outcome pathway (AOP) construct to organize, identify, and characterize human genetic susceptibility in HHRA. We explore how publicly available human genetic datasets can be used to gain mechanistic understanding of molecular events and characterize human susceptibility for an adverse outcome. We present a computational method that implements publicly available human genetic data to prioritize AOPs with potential for human genetic variability. We describe the application of this approach across multiple described AOPs for health outcomes of interest, and by focusing on a single molecular initiating event. This contributes to a long-term goal to improve estimates of human susceptibility for use in HHRA for single and multiple chemicals.

Barriers to the use of toxicogenomics data in human health risk assessment: A survey of Canadian risk assessors

Regulatory agencies worldwide need to modernize human health risk assessment (HHRA) to meet challenges of the 21st century. Toxicogenomics is at the core of this improvement. Today, however, the use of toxicogenomics data in HHRA is very limited. The purpose of this survey was to identify barriers to the application of toxicogenomics data in HHRA by human health risk assessors. An online survey targeting Canadian risk assessors gathered information on their knowledge and perception of toxicogenomics, their current and future inclusion of toxicogenomics data in HHRA, and barriers to the use of such data. Twenty-nine (29) participants completed a questionnaire after 2 months of solicitation. The results show that the application of toxicogenomics data in Canada is marginal, with 85% of respondents reporting that they never or rarely used such data. Knowledge of toxicogenomics by Canadian risk assessors is also limited: about two-thirds of respondents (68%) were not at all or only slightly familiar with the concept. Lack of guidelines for toxicogenomics data interpretation, data quality assessment and on their use in HHRA, were found to be major barriers. In conclusion, there is a need for interventions aimed at facilitating the use of toxicogenomics data in HHRA, when available.

The Use of PBPK Models to Inform Human Health Risk Assessment: Case Study on Perchlorate and Radioiodide Human Lifestage Models

Physiologically-based pharmacokinetic (PBPK) models are often submitted to or selected by agencies, such as the U.S. Environmental Protection Agency (U.S. EPA) and Agency for Toxic Substances and Disease Registry, for consideration for application in human health risk assessment (HHRA). Recently, U.S. EPA evaluated the human PBPK models for perchlorate and radioiodide for their ability to estimate the relative sensitivity of perchlorate inhibition on thyroidal radioiodide uptake for various population groups and lifestages. The most well-defined mode of action of the environmental contaminant, perchlorate, is competitive inhibition of thyroidal iodide uptake by the sodium-iodide symporter (NIS). In this analysis, a six-step framework for PBPK model evaluation was followed, and with a few modifications, the models were determined to be suitable for use in HHRA to evaluate relative sensitivity among human lifestages. Relative sensitivity to perchlorate was determined by comparing the PBPK model predicted percent inhibition of thyroidal radioactive iodide uptake (RAIU) by perchlorate for different lifestages. A limited sensitivity analysis indicated that model parameters describing urinary excretion of perchlorate and iodide were particularly important in prediction of RAIU inhibition; therefore, a range of biologically plausible values available in the peer-reviewed literature was evaluated. Using the updated PBPK models, the greatest sensitivity to RAIU inhibition was predicted to be the near-term fetus (gestation week 40) compared to the average adult and other lifestages; however, when exposure factors were taken into account, newborns were found to be populations that need further evaluation and consideration in a risk assessment for perchlorate.

A soil ingestion pilot study of a population following a traditional lifestyle typical of rural or wilderness areas

The relatively few soil ingestion studies underpinning the recommended soil ingestion rates for contaminated site human health risk assessments (HHRAs) that have been conducted to date assessed soil ingestion in children living in urban or suburban areas of the United States, and to a lesser extent, Europe. However, the lifestyle of populations living in North American urban and suburban environments is expected to involve limited direct contact with soil. Conversely, many populations, such as indigenous and Aboriginal peoples residing in rural and wilderness areas of North America and worldwide, participate in activities that increase the frequency of direct contact with soil. Qualitative exposure of Aboriginal populations inhabiting wilderness areas suggest that high levels of soil ingestion may occur that are many times greater than those recommended by regulatory agencies for use in HHRAs. Accordingly, a study of subjects selected from a wilderness community in Canada was conducted using mass balance tracer methods to estimate soil ingestion and the results compared with previous soil ingestion studies and regulatory guidelines for the soil ingestion rates used in HHRA of contaminated sites. A pilot study of 7 subjects living in the Nemiah Valley of British Columbia was conducted over a 3-week period. The mean soil ingestion rate estimated in this study using the 4 elemental tracers with the lowest food-to-soil ratios (i.e., Al, Ce, La, Si), was observed to be approximately 75mgd−1 (standard deviation 120mgd−1), the median soil ingestion rate was 50mgd−1, and the 90th percentile was 211mgd−1. These soil ingestion rate estimates are higher than the soil ingestion estimates currently recommended for HHRAs of adults, and higher than those obtained in most previous studies of adults. However, the estimates are lower than the earlier qualitative assessments of subsistence lifestyles.

Physiologically Based Pharmacokinetic Model Use in Risk Assessment—Why Being Published Is Not Enough

A panel of experts in physiologically based pharmacokinetic (PBPK) modeling and relevant quantitative methods was convened to describe and discuss model evaluation criteria, issues, and choices that arise in model application and computational tools for improving model quality for use in human health risk assessments (HHRAs). Although publication of a PBPK model in a peer-reviewed journal is a mark of good science, subsequent evaluation of published models and the supporting computer code is necessary for their consideration for use in HHRAs. Standardized model evaluation criteria and a thorough and efficient review process can reduce the number of review and revision iterations and hence the time needed to prepare a model for application. Efficient and consistent review also allows for rapid identification of needed model modifications to address HHRA-specific issues. This manuscript reports on the workshop where a process and criteria that were created for PBPK model review were discussed along with other issues related to model review and application in HHRA. Other issues include (1) model code availability, portability, and validity; (2) probabilistic (e.g., population-based) PBPK models and critical choices in parameter values to fully characterize population variability; and (3) approaches to integrating PBPK model outputs with other HHRA tools, including benchmark dose modeling. Two specific case study examples are provided to illustrate challenges that were encountered during the review and application process. By considering the frequent challenges encountered in the review and application of PBPK models during the model development phase, scientists may be better able to prepare their models for use in HHRAs.