Paraoxonase-1 (PON1) is a serum esterase that hydrolyzes the activated oxon form of several organophosphates. The central role of PON1 in detoxification of organophosphate (OP) pesticides was ...demonstrated in knockout mouse studies, suggesting that human variability in PON1 needs to be considered in health risk assessments involving exposure to these pesticides. The current analysis focused on two genetic loci in which polymorphisms demonstrated to affect PON1 activity. Detailed kinetic studies and population studies found that the *192Q (wild type) allele is more active toward some substrates (such as sarin, soman, and diazoxon) and less active toward others (such as paraoxon or chlorpyrifos) relative to the variant *192R allele. Another allele that affects activity is *55M; PON1 enzyme quantity, rather than specific activity or substrate preference, is altered. The *192R variant occurs commonly with a frequency of 25-64% across the populations analyzed. The *55M allele is less common, occurring in 5-40% of individuals depending upon the ethnic group studied. These activity and allele frequency data were incorporated into Monte Carlo simulations in which the frequency of both variant alleles was simultaneously modeled in Caucasian, African American, and Japanese populations. The resulting Monte Carlo activity distributions were bimodal for the substrate paraoxon with approximately fourfold differences between low- and high-activity modal medians. Differences in activity between total population median and 1st percentile were five- to sixfold. When sarin metabolic variability was simulated, the population distributions were unimodal. However, there was an even greater degree of interindividual variability (median to 1st percentile difference >20-fold). These results show that the combined effects of two PON1 allelic variants yielded a population distribution that is associated with a considerable degree of interindividual variability in enzyme activity. This indicates that assessments involving PON1 substrates need to evaluate polymorphism-related variability in enzyme activity to display the distribution of internal doses and adverse responses. This may best be achieved via physiologically based pharmacokinetic (PBPK) models that input PON1 activity distributions, such as those generated in this analysis, to simulate the range of oxon internal doses possible across the population.
Physiologically based pharmacokinetic (PBPK) models have increasingly been employed in chemical health risk assessments. By incorporating individual variability conferred by genetic polymorphisms, ...health conditions, and physiological changes during development and aging, PBPK models are ideal for predicting chemical disposition in various subpopulations of interest. In order to improve the parameterization of PBPK models for healthy and health-impaired elderly (herein defined as those aged 65 yr and older), physiological parameter values were obtained from the peer-reviewed literature, evaluated, and entered into a Microsoft ACCESS database. Database records include values for key age-specific model inputs such as ventilation rates, organ volumes and blood flows, glomerular filtration rates, and other clearance-related processes. In total, 528 publications were screened for relevant data, resulting in the inclusion of 155 publications comprising 1051 data records for healthy elderly adults and 115 data records for elderly with conditions such as diabetes, chronic obstructive pulmonary disease (COPD), obesity, heart disease, and renal disease. There are no consistent trends across parameters or their associated variance with age; the gross variance in body weight decreased with advancing age, whereas there was no change in variance for brain weight. The database contains some information to inform ethnic and gender differences in parameters; however, the majority of the published data pertain to Asian (mostly Japanese) and Caucasian males. As expected, the number of records tends to decrease with advancing age. In addition to a general lack of data for parameters in the elderly with various health conditions, there is also a dearth of information on blood and tissue composition in all elderly groups. Importantly, there are relatively few records for alveolar ventilation rate; therefore, the relationship between this parameter and cardiac output (usually assumed to be 1:1) in the elderly is not well informed by the database. Despite these limitations, the database represents a potentially useful resource for parameterizing PBPK models for the elderly to facilitate the prediction of dose metrics in older populations for application in risk assessment.
Background: Perchlorate is a common contaminant of drinking water and food. It competes with iodide for uptake into the thyroid, thus interfering with thyroid hormone production. The U.S. ...Environmental Protection Agency's Office of Solid Waste and Emergency Response (OSWER) set a groundwater preliminary remediation goal (PRG) of 24.5 µg/L to prevent exposure of pregnant women that would affect the fetus. This does not account for the greater exposure that is possible in nursing infants or for the relative source contribution (RSC), a factor normally used to lower the PRG due to nonwater exposures. Objectives: Our goal was to assess whether the OSWER PRG protects infants against exposures from breast-feeding, and to evaluate the perchlorate RSC. Methods: We used Monte Carlo analysis to simulate nursing infant exposures associated with the OSWER PRG when combined with background perchlorate. Results: The PRG can lead to a 7-fold increase in breast milk concentration, causing 90% of nursing infants to exceed the reference dose (RfD) (average exceedance, 2.8-fold). Drinking-water perchlorate must be < 6.9 µg/L to keep the median, and < 1.3 µg/L to keep the 90th-percentile nursing infant exposure below the RfD. This is 3.6- to 19-fold below the PRG. Analysis of biomonitoring data suggests an RSC of 0.7 for pregnant women and of 0.2 for nursing infants. Recent data from the Centers for Disease Control and Prevention (CDC) suggest that the RfD itself needs to be reevaluated because of hormonal effects in the general population. Conclusions: The OSWER PRG for perchlorate can be improved by considering infant exposures, by incorporating an RSC, and by being responsive to any changes in the RfD resulting from the new CDC data.
In revising cancer risk assessment guidelines, the U.S. Environmental Protection Agency (EPA) analyzed animal cancer bioassay data over different periods of life. In this article, we report an ...improved analysis of these data (supplemented with some chemical carcinogenesis observations not included in the U.S. EPA's original analysis) and animal bioassay studies of ionizing radiation. We use likelihood methods to avoid excluding cases where no tumors were observed in specific groups. We express dosage for animals of different weights on a metabolically consistent basis (concentration in air or food, or per unit body weight to the three-quarters power). Finally, we use a system of dummy variables to represent exposures during fetal, preweaning, and weaning-60-day postnatal periods, yielding separate estimates of relative sensitivity per day of dosing in these intervals. Central estimate results indicate a 5- to 60-fold increased carcinogenic sensitivity in the birth-weaning period per dose + (body weight0.75-day) for mutagenic carcinogens and a somewhat smaller increase-centered about 5-fold-for radiation carcinogenesis per gray. Effects were greater in males than in females. We found a similar increased sensitivity in the fetal period for direct-acting nitrosoureas, but no such increased fetal sensitivity was detected for carcinogens requiring metabolic activation. For the birth-weaning period, we found an increased sensitivity for direct administration to the pups similar to that found for indirect exposure via lactation. Radiation experiments indicated that carcinogenic sensitivity is not constant through the "adult" period, but the dosage delivered in 12- to 21-month-old animals appears a few-fold less effective than the comparable dosage delivered in young adults (90-105 days of age).
In his letter, Rhomberg raises several issues concerning recommendations in our report of the workshop "Issues and Approaches to Low Dose-Response Extrapolation for Environmental Health Risk ...Assessment" (White et al. 2009). One recommendation of the workshop was to set aside the generally held presumption that dose--response functions should follow a threshold model when extrapolating from higher dose studies of non-carcinogenic responses to lower dose levels typical for environmental exposures to chemicals. Workshop participants generally concluded that the selection of population-level low-dose extrapolation models should be informed by population factors such as interindividual variability in susceptibility and coexposures, as well as by categorization of mechanisms of toxicity. As indicated in the meeting report (White et al. 2009), most workshop participants preferred a linear, no-threshold approach to low-dose extrapolation modeling, combined with modeled estimates of the low range of observed data, for noncancer, as well as cancer, outcomes in the absence of convincing evidence to indicate that an alternative model is more appropriate. We recognize that this recommendation represents a departure from current generally accepted practice.
Dietary Reference Intakes (DRIs) are used in Canada and the United States in planning and assessing diets of apparently healthy individuals and population groups. The approaches used to establish ...DRIs on the basis of classical nutrient deficiencies and/or toxicities have worked well. However, it has proved to be more challenging to base DRI values on chronic disease endpoints; deviations from the traditional framework were often required, and in some cases, DRI values were not established for intakes that affected chronic disease outcomes despite evidence that supported a relation. The increasing proportions of elderly citizens, the growing prevalence of chronic diseases, and the persistently high prevalence of overweight and obesity, which predispose to chronic disease, highlight the importance of understanding the impact of nutrition on chronic disease prevention and control. A multidisciplinary working group sponsored by the Canadian and US government DRI steering committees met from November 2014 to April 2016 to identify options for addressing key scientific challenges encountered in the use of chronic disease endpoints to establish reference values. The working group focused on 3 key questions: 1) What are the important evidentiary challenges for selecting and using chronic disease endpoints in future DRI reviews, 2) what intake-response models can future DRI committees consider when using chronic disease endpoints, and 3) what are the arguments for and against continuing to include chronic disease endpoints in future DRI reviews? This report outlines the range of options identified by the working group for answering these key questions, as well as the strengths and weaknesses of each option.
The Next Generation (NexGen) of Risk Assessment effort is a multi-year collaboration among several organizations evaluating new, potentially more efficient molecular, computational, and systems ...biology approaches to risk assessment. This article summarizes our findings, suggests applications to risk assessment, and identifies strategic research directions.
Our specific objectives were to test whether advanced biological data and methods could better inform our understanding of public health risks posed by environmental exposures.
New data and methods were applied and evaluated for use in hazard identification and dose-response assessment. Biomarkers of exposure and effect, and risk characterization were also examined. Consideration was given to various decision contexts with increasing regulatory and public health impacts. Data types included transcriptomics, genomics, and proteomics. Methods included molecular epidemiology and clinical studies, bioinformatic knowledge mining, pathway and network analyses, short-duration in vivo and in vitro bioassays, and quantitative structure activity relationship modeling.
NexGen has advanced our ability to apply new science by more rapidly identifying chemicals and exposures of potential concern, helping characterize mechanisms of action that influence conclusions about causality, exposure-response relationships, susceptibility and cumulative risk, and by elucidating new biomarkers of exposure and effects. Additionally, NexGen has fostered extensive discussion among risk scientists and managers and improved confidence in interpreting and applying new data streams.
While considerable uncertainties remain, thoughtful application of new knowledge to risk assessment appears reasonable for augmenting major scope assessments, forming the basis for or augmenting limited scope assessments, and for prioritization and screening of very data limited chemicals. Citation: Cote I, Andersen ME, Ankley GT, Barone S, Birnbaum LS, Boekelheide K, Bois FY, Burgoon LD, Chiu WA, Crawford-Brown D, Crofton KM, DeVito M, Devlin RB, Edwards SW, Guyton KZ, Hattis D, Judson RS, Knight D, Krewski D, Lambert J, Maull EA, Mendrick D, Paoli GM, Patel CJ, Perkins EJ, Poje G, Portier CJ, Rusyn I, Schulte PA, Simeonov A, Smith MT, Thayer KA, Thomas RS, Thomas R, Tice RR, Vandenberg JJ, Villeneuve DL, Wesselkamper S, Whelan M, Whittaker C, White R, Xia M, Yauk C, Zeise L, Zhao J, DeWoskin RS. 2016. The Next Generation of Risk Assessment multiyear study-highlights of findings, applications to risk assessment, and future directions. Environ Health Perspect 124:1671-1682; http://dx.doi.org/10.1289/EHP233.
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