Angiotensin-(1-9) prevents vascular remodeling by decreasing vascular smooth muscle cell dedifferentiation through a FoxO1-dependent mechanism.

The renin-angiotensin system, one of the main regulators of vascular function, controls vasoconstriction, inflammation and vascular remodeling. Antagonistic actions of the counter-regulatory renin-angiotensin system, which include vasodilation, anti-proliferative, anti-inflammatory and anti-remodeling effects, have also been described. However, little is known about the direct effects of angiotensin-(1-9), a peptide of the counter-regulatory renin-angiotensin system, on vascular smooth muscle cells. Here, we studied the anti-vascular remodeling effects of angiotensin-(1-9), with special focus on the control of vascular smooth muscle cell phenotype. Angiotensin-(1-9) decreased blood pressure and aorta media thickness in spontaneously hypertensive rats. Reduction of media thickness was associated with decreased vascular smooth muscle cell proliferation. In the A7r5 VSMC cell line and in primary cultures of rat aorta smooth muscle cells, angiotensin-(1-9) did not modify basal proliferation. However, angiotensin-(1-9) inhibited proliferation, migration and contractile protein decrease induced by platelet derived growth factor-BB. Moreover, angiotensin-(1-9) reduced Akt and FoxO1 phosphorylation at 30 min, followed by an increase of total FoxO1 protein content. Angiotensin-(1-9) effects were blocked by the AT2R antagonist PD123319, Akt-Myr overexpression and FoxO1 siRNA. These data suggest that angiotensin-(1-9) inhibits vascular smooth muscle cell dedifferentiation by an AT2R/Akt/FoxO1-dependent mechanism.

Focusing on children's inhalation dosimetry and health effects for risk assessment: an introduction.

Substantial effort has been invested in improving children's health risk assessment in recent years. However, the body of scientific evidence in support of children's health assessment is constantly advancing, indicating the need for continual updating of risk assessment methods. Children's inhalation dosimetry and child-specific adverse health effects are of particular concern for risk assessment. When focusing on this topic within children's health, key issues for consideration include (1) epidemiological evidence of adverse effects following children's exposure to air pollution, (2) ontogeny of the lungs and effects on dosimetry, (3) estimation and variability of children's inhalation rates, and (4) current risk assessment methodologies for addressing children. In this article, existing and emerging information relating to these key issues are introduced and discussed in an effort to better understand children's inhalation dosimetry and adverse health effects for risk assessment. While much useful evidence is currently available, additional research and methods are warranted for improved children's health risk assessment.

A lifestage approach to assessing children's exposure.

Understanding and characterizing risks to children has been the focus of considerable research efforts at the U.S. Environmental Protection Agency (EPA). Potential health risks resulting from environmental exposures before conception and during pre- and postnatal development are often difficult to recognize and assess because of a potential time lag between the relevant periods of exposure during development and associated outcomes that may be expressed at later lifestages. Recognizing this challenge, a lifestage approach for assessing exposure and risk is presented in the recent EPA report titled A Framework for Assessing Health Risks of Environmental Exposures to Children (U.S. EPA, 2006). This EPA report emphasizes the need to account for the potential exposures to environmental agents during all stages of development, and consideration of the relevant adverse health outcomes that may occur as a result of such exposures. It identifies lifestage-specific issues associated with exposure characterization for regulatory risk assessment, summarizes the lifestage-specific approach to exposure characterization presented in the Framework, and discusses emerging research needs for exposure characterization in the larger public-health context. This lifestage approach for characterizing children's exposures to environmental contaminants ensures a more complete evaluation of the potential for vulnerability and exposure of sensitive populations throughout the life cycle.

Estimates of fish consumption rates for consumers of bought and self-caught fish in Connecticut, Florida, Minnesota, and North Dakota.

Fish consumption rates derived from national surveys may not accurately reflect consumption rates in a particular population such as recreational anglers. Many state and local health agencies in the U.S. have conducted area-specific surveys to study fish consumption patterns in local populations, assess exposure to environmental contaminants, or evaluate compliance with fish advisories. The U.S. Environmental Protection Agency (EPA) has analyzed the raw data from fish consumption surveys in Florida, Connecticut, Minnesota, and North Dakota for the purpose of deriving distributions of fish consumption rates and studying the variables that may be more predictive of high-end consumers. Distributions of fish consumption for different age cohorts, ethnic groups, socioeconomic statuses, types of fish (i.e., freshwater, marine, estuarine), and source of fish (i.e., store-bought versus self-caught) were derived. Consumption of fish and shellfish for those who consume both caught and bought fish is higher than those who reported eating only bought or only self-caught. Mean fish consumption per kilogram of body weight ranged from 0.11 g/kg-day to 2.3 g/kg-day. The highest values were observed in Florida for children 1<6 years of age. The Florida data show a statistically significant increase in the percentage of the population reporting fish and shellfish consumption with an increase in household income and education. This trend was not observed in the other states.

Frequency of mouthing behavior in young children.

Young children may be more likely than adults to be exposed to pesticides following a residential application as a result of hand- and object-to-mouth contacts in contaminated areas. However, relatively few studies have specifically evaluated mouthing behavior in children less than 5 years of age. Previously unpublished data collected by the Fred Hutchinson Cancer Research Center (FHCRC) were analyzed to assess the mouthing behavior of 72 children (37 males/35 females). Total mouthing behavior data included the daily frequency of both mouth and tongue contacts with hands, other body parts, surfaces, natural objects, and toys. Eating events were excluded. Children ranged in age from 11 to 60 months. Observations for more than 1 day were available for 78% of the children. The total data set was disaggregated by gender into five age groups (10-20, 20-30, 30-40, 40-50, 50-60 months). Statistical analyses of the data were then undertaken to determine if significant differences existed among the age/gender subgroups in the sample. A mixed effects linear model was used to test the associations among age, gender, and mouthing frequencies. Subjects were treated as random and independent, and intrasubject variability was accounted for with an autocorrelation function. Results indicated that there was no association between mouthing frequency and gender. However, a clear relationship was observed between mouthing frequency and age. Using a tree analysis, two distinct groups could be identified: children < or = 24 and children >24 months of age. Children < or = 24 months exhibited the highest frequency of mouthing behavior with 81+/-7 events/h (mean+/-SE) (n=28 subjects, 69 observations). Children >24 months exhibited the lowest frequency of mouthing behavior with 42+/-4 events/h (n=44 subjects, 117 observations). These results suggest that children are less likely to place objects into their mouths as they age. These changes in mouthing behavior as a child ages should be accounted for when assessing aggregate exposure to pesticides in the residential environment.

Overview of the use of the U.S. EPA exposure factors handbook.

Risk assessments are important components of the decision making process. At hazardous waste sites, they are used as tools to determine appropriate cleanup levels. Therefore, it is critical that the best up-to-date methods, models, and exposure data are available to the exposure and risk assessor to realistically estimate the potential for human and ecological exposures to environmental contaminants. The EPA Exposure Factors Handbook published in 1997 is a tool available to exposure assessors which summarizes statistical data on exposure factors necessary to conduct human health exposure assessments. Since it was first published by EPA in 1989, the handbook has been the primary source of data for human exposure assessments. The purpose of this paper is to provide an overview of the handbook, its impact, applications, discussion about data gaps, and future directions.

A review of soil and dust ingestion studies for children.

Soil and dust ingestion by children may be important pathways of exposure to environmental contaminants. Contaminated soil and dust may end up on children's hands and objects, because they play close to the ground. These contaminants can be ingested by children, because they have a tendency to place objects, including their fingers, in their mouths. Assessing exposure through this pathway requires information about the amount of soil and dust ingested by children. Estimates of soil and dust ingestion and information on the prevalence of the behavior have been published in the literature, but research in this area is generally limited. Three methodologies have been used to quantify soil and dust ingestion rates. In this paper, these are referred to as the tracer element method, the biokinetic model comparison method, and the activity pattern method. This paper discusses the information available on the prevalence of soil and dust ingestion behavior, summarizes the three methodologies for quantifying soil and dust ingestion, and discusses their limitations. Soil ingestion data derived from studies that use these methodologies are also summarized. Although they are based on different estimation approaches, the central tendency estimates of soil and dust ingestion derived from the three methodologies are generally comparable.

Exposure factors resources: contrasting EPA's Exposure Factors Handbook with international sources.

Efforts to compile and standardize human exposure factors have resulted in the development of a variety of resources available to the scientific community. For example, the US Environmental Protection Agency (EPA) developed the Exposure Factors Handbook and Child-specific Exposure Factors Handbook to promote consistency among its various exposure-assessment activities. The US EPA handbooks are compilations of human exposure factors data, including anthropometric and sociocultural data (e.g., body weights, skin-surface areas, and life expectancy), behavioral data (e.g., non-dietary ingestion rates, activity/time use patterns, and consumer product use), factors that may be influenced by the physiological needs of the body, metabolic activity, and health and weight status (e.g., water and food intake, and inhalation rates), and other factors (e.g., building characteristics). Other countries have engaged in similar efforts to compile and standardize exposure factors for use in exposure and risk assessments. For example, the ExpoFacts database contains data for 30 European Union countries. Australia, Canada, Japan, Korea, and Taiwan have developed, or are developing, documents that provide exposure factors data relevant to their populations. The purpose of this paper is to provide an overview of some of the available exposure factors resources; to explore some of the similarities and differences between the US EPA Exposure Factors Handbook and selected other international resources, and to highlight data gaps and present some considerations for promoting consistency among these resources.

A review of physiological and behavioral changes during pregnancy and lactation: potential exposure factors and data gaps.

Exposures to environmental contaminants can pose risks to pregnant women's health, their developing fetuses, children, and adults later in their lives. Assessing risks to this potentially susceptible population requires a sound understanding of the physiological and behavioral changes that occur during pregnancy and lactation. Many physiological and anatomical changes occur in a woman's organ systems during the course of pregnancy and lactation. For example, blood volume and cardiac output increase during pregnancy, and other metabolic functions are altered to provide for the demands of the fetus. During lactation, nutritional demands are greater than during pregnancy. There are also changes in behavior during both pregnancy and lactation. For example, water consumption during pregnancy and lactation increases. These behavioral and physiological changes can lead to different environmental exposures than these women might otherwise experience in the absence of pregnancy or lactation. This paper provides a summary of information from the published literature related to behavioral and physiological changes in pregnant and lactating women that may affect their exposure or susceptibility to environmental contaminants, provides potentially useful exposure factor data for this population of women, and highlights data gaps.

The evolution of EPA's Exposure Factors Handbook and its future as an exposure assessment resource.

The need to compile and summarize exposure factors data into a resource document was first established in 1983 after the publication of the National Academy of Sciences (NAS) report on Risk Assessment in the Federal Government: Managing the Process and subsequent publication of the Environmental Protection Agency's (EPA's) exposure guidelines in 1986 (NAS, 1983; US EPA, 1986). During the same time frame, the EPA published a report entitled Development of Statistical Distributions or Ranges of Standard Factors Used in Exposure Assessment to promote consistency among various exposure assessment activities in which EPA was involved and to serve as a support document to the 1986 exposure guidelines (US EPA, 1985). As the exposure assessment field continued to advance during the 1980s and 1990s, so did the need for more comprehensive data on exposure factors. The Exposure Factors Handbook was first published in 1989 in response to this need (US EPA, 1989). It became an important reference document and has been revised and updated since its original publication (US EPA, 1989; US EPA, 1997a; US EPA, 2011a). This paper reviews the evolution of the Exposure Factors Handbook, and explores anticipated needs and some of the potential options for future updates of the handbook.

Consideration of age-related changes in behavior trends in older adults in assessing risks of environmental exposures.

OBJECTIVE: To explore age-related behavior differences between older and younger adults, and to review how older adult activity patterns are considered in evaluating the potential risk of exposure to environmental pollutants. METHODS: Activity pattern data and their use in risk assessments were analyzed using the U.S. EPA Exposure Factors Handbook (EFH), U.S. EPA Consolidated Human Activity Pattern Database (CHAD), and peer-reviewed literature describing human health risk assessments. RESULTS: The characterization by age of some factors likely to impact older adults' exposures remains limited. We demonstrate that age-related behavior trends vary between younger and older adults, and these differences are rarely explicitly considered in environmental health risk assessment for older adults. DISCUSSION: Incorporating older adult exposure factors into risk assessments may be challenging because of data gaps and difficulty in defining and appropriately binning older adults. Additional data related to older adult exposure factors are warranted for evaluating risk among this susceptible population.

Estimated long-term fish and shellfish intake--national health and nutrition examination survey.

Usual intake estimates describe long-term average intake of food and nutrients and food contaminants. The frequencies of fish and shellfish intake over a 30-day period from National Health and Examination Survey (NHANES 1999-2006) were combined with 24-h dietary recall data from NHANES 2003-2004 using a Monte Carlo procedure to estimate the usual intake of fish and shellfish in this study. Usual intakes were estimated for the US population including children 1 to <11 years, males/females 11 to <16 years, 16 to <21 years, and adults 21+ years. Estimated mean fish intake (consumers only) was highest among children 1 to <2 years and 2 to <3 years, at 0.37 g/kg-day for both age groups, and lowest for females 11 to <16 years, at 0.13 g/kg-day. In all age groups, daily intake estimates were highest for breaded fish, salmon, and mackerel. Among children and teenage consumers, tuna, salmon, and breaded fish were the most frequently consumed fish; shrimp, scallops, and crabs were the most frequently consumed shellfish. The intake estimates from this study better reflect long-term average intake rates and are preferred to assess long-term intake of nutrients and possible exposure to environmental contaminants from fish and shellfish sources than 2-day average estimates.

Estimation of age-specific per capita home-produced food intake among populations that garden, farm, or raise animals.

Intake of home-produced foods may be a concern in areas where chemical contamination exists. Estimating exposure to contaminants in home-produced foods requires knowledge of the amount of these foods consumed. The US Environmental Protection Agency's (US EPA's) Exposure Factors Handbook provides data on consumption of home-produced foods based on the US Department of Agriculture's (USDA's) 1987-1988 Nationwide Food Consumption Survey (NFCS), the most recent national food survey that contains the information necessary to estimate home-produced consumption. These data represent "consumer-only" intake rate distributions for various age and demographic categories. "Consumers-only" information is also provided for households who garden, farm, and raise animals for all age groups combined. However, these "consumer-only" values may not always be appropriate when assessing chronic exposures. Furthermore, data for all ages combined may not be useful for estimating exposure among age groups that may be of particular concern. This paper provides age-specific "per capita" intake rate distributions of home-produced foods specifically for the populations that garden, farm, and raise animals, using data from EPA's Exposure Factors Handbook.

A meta-analysis of children's object-to-mouth frequency data for estimating non-dietary ingestion exposure.

To improve estimates of non-dietary ingestion in probabilistic exposure modeling, a meta-analysis of children's object-to-mouth frequency was conducted using data from seven available studies representing 438 participants and approximately 1500 h of behavior observation. The analysis represents the first comprehensive effort to fit object-to-mouth frequency variability and uncertainty distributions by indoor/outdoor location and by age groups recommended by the US Environmental Protection Agency for assessing childhood exposures. Weibull distributions best fit the observed data from studies with no statistical differences, and are presented by study, age group, and location. As age increases, both indoor and outdoor object-to-mouth frequencies decrease. Object-to-mouth frequency is significantly greater indoors (2-32 contacts/h) than outdoors (average 1-9 contacts/h). This paper compares results to a similar hand-to-mouth frequency meta-analysis. Children who tend to mouth hands indoors also tend to mouth hands outdoors; children who tend to mouth objects indoors tend to mouth objects outdoors. However, children who tend to mouth objects do not necessarily have a tendency to mouth hands. Unlike for hand-to-mouth frequency, a statistical difference was found among the various studies for object-to-mouth frequency. This could be due to different definitions for object mouthing across the studies considered. The analysis highlights the need for additional object-to-mouth data (indoors and especially outdoors) for various age groups using standardized collection and analysis.

Identifying childhood age groups for exposure assessments and monitoring.

The purpose of this article is to describe a standard set of age groups for exposure assessors to consider when assessing childhood exposure and potential dose to environmental contaminants. In addition, this article presents examples to show how the age groups can be applied in children's exposure assessments. A consistent set of childhood age groups, supported by an underlying scientific rationale, will improve the accuracy and comparability of exposure and risk assessments for children. The effort was undertaken in part to aid the U.S. Environmental Protection Agency (EPA) in implementing such regulatory initiatives as the 1997 Presidential Executive Order 13,045, which required all federal agencies to ensure that their standards take into account special risks to children. The standard age groups include: birth to <1 month; 1 to <3 months; 3 to <6 months; 6 to <12 months; 1 to <2 years; 2 to <3 years; 3 to <6 years; 6 to <11 years; 11 to <16 years; and 16 to <21 years. These age groups reflect a consideration of developmental changes in various behavioral, anatomical, and physiological characteristics that impact exposure and potential dose. It is expected that the availability of a standard set of early-life age groups will inform future analyses of exposure factors data as well as guide new research and data collection efforts to fill knowledge gaps.

A meta-analysis of children's hand-to-mouth frequency data for estimating nondietary ingestion exposure.

Because of their mouthing behaviors, children have a higher potential for exposure to available chemicals through the nondietary ingestion route; thus, frequency of hand-to-mouth activity is an important variable for exposure assessments. Such data are limited and difficult to collect. Few published studies report such information, and the studies that have been conducted used different data collection approaches (e.g., videography versus real-time observation), data analysis and reporting methods, ages of children, locations, and even definitions of "mouthing." For this article, hand-to-mouth frequency data were gathered from 9 available studies representing 429 subjects and more than 2,000 hours of behavior observation. A meta-analysis was conducted to study differences in hand-to-mouth frequency based on study, age group, gender, and location (indoor vs. outdoor), to fit variability and uncertainty distributions that can be used in probabilistic exposure assessments, and to identify any data gaps. Results of this analysis indicate that age and location are important for hand-to-mouth frequency, but study and gender are not. As age increases, both indoor and outdoor hand-to-mouth frequencies decrease. Hand-to-mouth behavior is significantly greater indoors than outdoors. For both indoor and outdoor hand-to-mouth frequencies, interpersonal, and intra-personal variability are approximately 60% and approximately 30%, respectively. The variance difference among different studies is much bigger than its mean, indicating that different studies with different methodologies have similar central values. Weibull distributions best fit the observed data for the different variables considered and are presented in this article by study, age group, and location. Average indoor hand-to-mouth behavior ranged from 6.7 to 28.0 contacts/hour, with the lowest value corresponding to the 6 to <11 year olds and the highest value corresponding to the 3 to <6 month olds. Average outdoor hand-to-mouth frequency ranged from 2.9 to 14.5 contacts/hour, with the lowest value corresponding to the 6 to <11 year olds and the highest value corresponding to the 6 to <12 month olds. The analysis highlights the need for additional hand-to-mouth data for the <3 months, 3 to <6 months, and 3 to <6 year age groups using standardized collection and analysis because of lack of data or high uncertainty in available data. This is the first publication to report Weibull distributions as the best fitting distribution for hand-to-mouth frequency; using the best fitting exposure factor distribution will help improve estimates of exposure. The analyses also represent a first comprehensive effort to fit hand-to-mouth frequency variability and uncertainty distributions by indoor/outdoor location and by age groups, using the new standard set of age groups recommended by the U.S. Environmental Protection Agency for assessing childhood exposures. Thus, the data presented in this article can be used to update the U.S. EPA's Child-Specific Exposure Factors Handbook and to improve estimates of nondietary ingestion in probabilistic exposure modeling.

Children's behavior and physiology and how it affects exposure to environmental contaminants.

Infant, child, and adolescent exposures to environmental toxicants are different from those of adults because of differences in behavior and physiology. Because of these differences, there is the potential for quantitatively different exposures at various stages of development. Pediatricians are well aware of these behavioral and physiologic differences from a clinical standpoint--namely, food and water intake, soil ingestion, mouthing behavior, inhalation physiology, and activity level--as they relate to the ratio of these parameters between the adult and the child when considering weight and surface area. Pediatricians recognized the importance of pica as a cause of lead poisoning, the noxious effect of second-hand smoke, and the greater propensity for addiction during the adolescent years. For determining the differences in impact of many environmental toxicants between adults and children, research is needed to document where and whether these differences result in deleterious effects.