A framework and case studies for evaluation of enzyme ontogeny in children's health risk evaluation.

Knowledge of the ontogeny of Phase I and Phase II metabolizing enzymes may be used to inform children's vulnerability based upon likely differences in internal dose from xenobiotic exposure. This might provide a qualitative assessment of toxicokinetic (TK) variability and uncertainty pertinent to early lifestages and help scope a more quantitative physiologically based toxicokinetic (PBTK) assessment. Although much is known regarding the ontogeny of metabolizing systems, this is not commonly utilized in scoping and problem formulation stage of human health risk evaluation. A framework is proposed for introducing this information into problem formulation which combines data on enzyme ontogeny and chemical-specific TK to explore potential child/adult differences in internal dose and whether such metabolic differences may be important factors in risk evaluation. The framework is illustrated with five case study chemicals, including some which are data rich and provide proof of concept, while others are data poor. Case studies for toluene and chlorpyrifos indicate potentially important child/adult TK differences while scoping for acetaminophen suggests enzyme ontogeny is unlikely to increase early-life risks. Scoping for trichloroethylene and aromatic amines indicates numerous ways that enzyme ontogeny may affect internal dose which necessitates further evaluation. PBTK modeling is a critical and feasible next step to further evaluate child-adult differences in internal dose for a number of these chemicals.

Pesticide data program: 30 years of food residue data and trends.

The USDA's Pesticide Data Program (PDP) celebrated its 30th anniversary in 2021 and is one of the world's largest monitoring programs for pesticide residues. The PDP database contains over 42 million data points for a pesticide paired to a commodity that have resulted from the analysis of nearly 310,000 food samples of 126 different commodities. Over the decades of the program, sampling methods and infrastructure, major milestones, developments, and accomplishments have unfolded. Comparisons of data for four commodities that were in the program early on illustrate that over time pesticide residues on foods change, particularly when new pesticides are registered, and updated data, such as those provided by PDP, are key for exposure and risk assessment.

Options for incorporating children's inhaled dose into human health risk assessment.

Increasing attention has been placed on inhalation dosimetry in children because of children's greater air intake rate and unique windows of vulnerability for various toxicants and health outcomes. However, risk assessments have not incorporated this information because dosimetric adjustments have focused upon extrapolation across species rather than across age groups within the human population. The objectives of this study were to synthesize information regarding child/adult intake and dosimetry differences for particles and gases for potential application to risk assessment. Data and models gathered at a 2006 workshop and more recent studies were reviewed to better understand lung development and inhaled dose in children. The results show that child/adult differences exist both on a chemical intake basis and on a deposited or systemic dose basis. These differences can persist for several years and are not captured by standard intraspecies uncertainty factors or by USEPA's reference concentration (RfC) methodology. Options for incorporating children's inhalation exposures into human risk assessments include (1) 3-fold default air intake adjustment for the first 3 years of life with a reduced factor for older children; (2) superseding this default via simplified dosimetry models akin to USEPA's RfC methodology modified for children; (3) utilizing more sophisticated models with better anatomical and air flow descriptions; (4) running these models with input distributions to reflect interchild variability; (5) developing more advanced approaches involving imaging techniques and computational fluid dynamic (CFD) models. These options will enable children's inhaled dose to have a quantitative role in risk assessment that has been lacking and will establish a basis for ongoing research.

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.

Assessing the health effects and risks associated with children's inhalation exposures--asthma and allergy.

Adults and children may have different reactions to inhalation exposures due to differences in target tissue doses following similar exposures, and/or different stages in lung growth and development. In the case of asthma and allergy both the developing immune system and initial encounters with common allergens contribute to this differential susceptibility. Asthma, the most common chronic childhood disease, has significant public health impacts and is characterized by chronic lung inflammation, reversible airflow obstruction, and immune sensitization to allergens. Animal studies described here suggest that air pollutants exacerbate asthma symptoms and may also play a role in disease induction. Changes characteristic of asthma were observed in rhesus monkeys sensitized to house dust mite antigen (HDMA) as infants and exposed repeatedly thereafter to ozone (O3) and HDMA. O3 exposure compromised airway growth and development and exacerbated the allergen response to favor intermittent airway obstruction and wheeze. In Brown Norway rats a variety of air pollutants enhanced sensitization to HDMA such that symptoms elicited in response to subsequent allergen challenge were more severe. Although useful for assessing air pollutants effects on initial sensitization, the rodent immune system is immature at birth relative to humans, making this model less useful for studying differential effects between adults and children. Because computational models available to address children's inhalation exposures are limited, default adjustments and their associated uncertainty will continue to be used in children's inhalation risk assessment. Because asthma is a complex (multiple genes, phenotypes, organ systems) disease, this area is ripe for systems biology approaches.

Approaches to Children's Exposure Assessment: Case Study with Diethylhexylphthalate (DEHP).

Children's exposure assessment is a key input into epidemiology studies, risk assessment and source apportionment. The goals of this article are to describe a methodology for children's exposure assessment that can be used for these purposes and to apply the methodology to source apportionment for the case study chemical, diethylhexylphthalate (DEHP). A key feature is the comparison of total (aggregate) exposure calculated via a pathways approach to that derived from a biomonitoring approach. The 4-step methodology and its results for DEHP are: (1) Prioritization of life stages and exposure pathways, with pregnancy, breast-fed infants, and toddlers the focus of the case study and pathways selected that are relevant to these groups; (2) Estimation of pathway-specific exposures by life stage wherein diet was found to be the largest contributor for pregnant women, breast milk and mouthing behavior for the nursing infant and diet, house dust, and mouthing for toddlers; (3) Comparison of aggregate exposure by pathways vs biomonitoring-based approaches wherein good concordance was found for toddlers and pregnant women providing confidence in the exposure assessment; (4) Source apportionment in which DEHP presence in foods, children's products, consumer products and the built environment are discussed with respect to early life mouthing, house dust and dietary exposure. A potential fifth step of the method involves the calculation of exposure doses for risk assessment which is described but outside the scope for the current case study. In summary, the methodology has been used to synthesize the available information to identify key sources of early life exposure to DEHP.

Review and analysis of inhalation dosimetry methods for application to children's risk assessment.

Young children have a greater ventilation rate per body weight or pulmonary surface area as compared to adults. The implications of this difference for inhalation dosimetry and children's risk assessment were evaluated in runs of the U.S. Environmental Protection Agency (U.S. EPA) 1994 reference concentration (RfC) methodology and the ICRP 1994 inhalation dosimetry model. Dosimetry estimates were made for 3-mo-old children and adults for particles and Category 1 and 2 reactive gases in the following respiratory-tract regions: extrathoracic (ET), tracheobronchial (BB), bronchioles (bb), and pulmonary (PU). Systemic dosimetry estimates were made for nonreactive (Category 3) gases. Results suggest similar ET dosimetry for children and adults for all types of inhaled materials. BB dosimetry was also similar across age groups except that the dosimetry of ultrafine particles in this region was twofold greater in 3-mo-old children than in adults. In contrast, the bb region generally showed higher dosimetry of particles and gases in adults than in children. Particle dose in the PU region was two- to fourfold higher in 3-mo-old children, with the greatest child/adult difference occurring for submicron size particles. Particulate dosimetry estimates with the default RfC methodology were below those found with the ICRP model for both adults and children for submicrometer sized particles. There were no cases in which reactive gas dosimetry was substantially greater in the respiratory regions of 3-mo-old children. Estimates of systemic dose of Category 3 gases were greater in 3-mo-old children than in adults, especially for liver dose of metabolite for rapidly metabolized gases. These analyses support the approach of assuming twofold greater inhalation dose in children than adults, although there are cases in which this differential can be greater and others where it can be less.