Melanie A. Marty

The effects of fine particle components on respiratory hospital admissions in children.

Background Epidemiologic studies have demonstrated an association between acute exposure to ambient fine particles and both mortality and morbidity. Less is known about the relative impacts of the specific chemical constituents of particulate matter < 2.5 μm in aerodynamic diameter (PM2.5) on hospital admissions. Objective This study was designed to estimate the risks of exposure to PM2.5 and several species on hospital admissions for respiratory diseases among children. Data and Methods We obtained data on daily counts of hospitalizations for children < 19 and < 5 years of age for total respiratory diseases and several subcategories including pneumonia, acute bronchitis, and asthma for six California counties from 2000 through 2003, as well as ambient concentrations of PM2.5 and its constituents, including elemental carbon (EC), organic carbon (OC), and nitrates (NO3). We used Poisson regression to estimate risks while controlling for important covariates. Results We observed associations between several components of PM2.5 and hospitalization for all of the respiratory outcomes examined. For example, for total respiratory admissions for children < 19 years of age, the interquartile range for a 3-day lag of PM2.5, EC, OC, NO3, and sulfates was associated with an excess risk of 4.1% [95% confidence interval (CI), 1.8–6.4], 5.4% (95% CI, 0.8–10.3), 3.4% (95% CI, 1.1–5.7), 3.3% (95% CI, 1.1–5.5), and 3.0% (95% CI, 0.4–5.7), respectively. We also observed associations for several metals. Additional associations with several of the species, including potassium, were observed in the cool season. Conclusion Components of PM2.5 were associated with hospitalization for several childhood respiratory diseases including pneumonia, bronchitis, and asthma. Because exposure to components (e.g., EC, OC, NO3, and K) and their related sources, including diesel and gasoline exhaust, wood smoke, and other combustion sources, are ubiquitous in the urban environment, it likely represents an identifiable and preventable risk factor for hospitalization for children.

Differences Between Children and Adults: Implications for Risk Assessment at California EPA

The California legislature enacted a law requiring the California Environmental Protection Agency (Cal/EPA) Office of Environmental Health Hazard Assessment (OEHHA) to evaluate whether our risk assessment methodologies are adequately protective of infants and children. In addition both OEHHA and the California Air Resources Board must examine whether the Ambient Air Quality Standards set for criteria air pollutants and the health values developed for air toxics are adequately protective of infants and children. We have initiated a program to look at potential differences in response to toxicants between children and adults. We are evaluating this issue from the perspective of exposure differences as well as toxicokinetic and toxicodynamic differences between children and adults. Data on specific chemicals are rather limited. As a result, we will be pooling information to determine whether there are generic differences between children and adults that may be applicable to risk assessment in general or to risk assessment of specific classes of compounds. This paper discusses the rationale for approaching the issue of determining whether our risk assessment methods are adequate for infants and children and includes a discussion of some of the available information on both qualitative and quantitative differences in response to toxicants between children and adults or immature and mature laboratory animals. We provide examples of differences between children and adults in absorption, metabolism, and excretion of toxicants as well as qualitative differences in toxic response.

Impact of environmental chemicals on lung development.

Background Disruption of fundamental biologic processes and associated signaling events may result in clinically significant alterations in lung development. Objectives We reviewed evidence on the impact of environmental chemicals on lung development and key signaling events in lung morphogenesis, and the relevance of potential outcomes to public health and regulatory science. Data sources We evaluated the peer-reviewed literature on developmental lung biology and toxicology, mechanistic studies, and supporting epidemiology. Data synthesis Lung function in infancy predicts pulmonary function throughout life. In utero and early postnatal exposures influence both childhood and adult lung structure and function and may predispose individuals to chronic obstructive lung disease and other disorders. The nutritional and endogenous chemical environment affects development of the lung and can result in altered function in the adult. Studies now suggest that similar adverse impacts may occur in animals and humans after exposure to environmentally relevant doses of certain xenobiotics during critical windows in early life. Potential mechanisms include interference with highly conserved factors in developmental processes such as gene regulation, molecular signaling, and growth factors involved in branching morphogenesis and alveolarization. Conclusions Assessment of environmental chemical impacts on the lung requires studies that evaluate specific alterations in structure or function—end points not regularly assessed in standard toxicity tests. Identifying effects on important signaling events may inform protocols of developmental toxicology studies. Such knowledge may enable policies promoting true primary prevention of lung diseases. Evidence of relevant signaling disruption in the absence of adequate developmental toxicology data should influence the size of the uncertainty factors used in risk assessments.

Focusing on Children's Inhalation Dosimetry and Health Effects for Risk Assessment: An Introduction

Substantial effort has been invested in improving childrens health risk assessment in recent years. However, the body of scientific evidence in support of childrens health assessment is constantly advancing, indicating the need for continual updating of risk assessment methods. Childrens inhalation dosimetry and child-specific adverse health effects are of particular concern for risk assessment. When focusing on this topic within childrens health, key issues for consideration include (1) epidemiological evidence of adverse effects following childrens exposure to air pollution, (2) ontogeny of the lungs and effects on dosimetry, (3) estimation and variability of childrens 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 childrens inhalation dosimetry and adverse health effects for risk assessment. While much useful evidence is currently available, additional research and methods are warranted for improved childrens health risk assessment.

Project TENDR: Targeting Environmental Neuro-Developmental Risks The TENDR Consensus Statement.

Summary: Children in America today are at an unacceptably high risk of developing neurodevelopmental disorders that affect the brain and nervous system including autism, attention deficit hyperactivity disorder, intellectual disabilities, and other learning and behavioral disabilities. These are complex disorders with multiple causes—genetic, social, and environmental. The contribution of toxic chemicals to these disorders can be prevented. Approach: Leading scientific and medical experts, along with children’s health advocates, came together in 2015 under the auspices of Project TENDR: Targeting Environmental Neuro-Developmental Risks to issue a call to action to reduce widespread exposures to chemicals that interfere with fetal and children’s brain development. Based on the available scientific evidence, the TENDR authors have identified prime examples of toxic chemicals and pollutants that increase children’s risks for neurodevelopmental disorders. These include chemicals that are used extensively in consumer products and that have become widespread in the environment. Some are chemicals to which children and pregnant women are regularly exposed, and they are detected in the bodies of virtually all Americans in national surveys conducted by the U.S. Centers for Disease Control and Prevention. The vast majority of chemicals in industrial and consumer products undergo almost no testing for developmental neurotoxicity or other health effects. Conclusion: Based on these findings, we assert that the current system in the United States for evaluating scientific evidence and making health-based decisions about environmental chemicals is fundamentally broken. To help reduce the unacceptably high prevalence of neurodevelopmental disorders in our children, we must eliminate or significantly reduce exposures to chemicals that contribute to these conditions. We must adopt a new framework for assessing chemicals that have the potential to disrupt brain development and prevent the use of those that may pose a risk. This consensus statement lays the foundation for developing recommendations to monitor, assess, and reduce exposures to neurotoxic chemicals. These measures are urgently needed if we are to protect healthy brain development so that current and future generations can reach their fullest potential.

Development of TEFs for PCB congeners by using an alternative biomarker--thyroid hormone levels.

Polychlorinated biphenyls (PCBs) are ubiquitous toxic contaminants. Health risk assessment for this class of chemicals is complex: the current toxic equivalency factor (TEF) method covers dioxin-like (DL-) PCBs, dibenzofurans, and dioxins, but excludes non-DL-PCBs. To address this deficiency, we evaluated published data for several PCB congeners to determine common biomarkers of effect. We found that the most sensitive biomarkers for DL-non-ortho-PCB 77 and PCB 126 are liver enzyme (e.g., ethoxyresorufin-O-deethylase, EROD) induction, circulating thyroxine (T4) decrease, and brain dopamine (DA) elevation. For DL-ortho-PCB 118 and non-DL-ortho-PCB 28 and PCB 153, the most sensitive biomarkers are brain DA decrease and circulating T4 decrease. The only consistent biomarker for both DL- and non-DL-PCBs is circulating T4 decrease. The calculated TEF-(TH), based on the effective dose to decrease T4 by 30% (ED(30)) with reference to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is identical to both TEF-(WHO98) and TEF-(WHO05) for TCDD and DL-PCBs (correlation coefficients are r=1.00, P<0.001; and r=0.99, P<0.001, respectively). We conclude that T4 decrease is a prospective biomarker for generating a new TEF scheme which includes some non-DL-congeners. The new TEF-(TH) parallels the TEF-(WHO) for DL-PCBs and, most importantly, is useful for non-DL-PCBs in risk assessment to address thyroid endocrine disruption and potentially the neurotoxic effects of PCBs.

Distribution of Daily Breathing Rates For Use in California's Air Toxics Hot Spots Program Risk Assessments

Data were combined from a study measuring breathing rates at various activities and two activity pattern studies to generate breathing rate distributions for children and adults. The children and adult breathing rate distributions were combined using a Monte Carlo technique to generate a breathing rate distribution for a lifetime spanning ages 0 to 70. The childrens breathing rate distribution has a mean, standard deviation, median and 95th percentile of 452, 67.7, 441, and 581 L/kg-day, respectively. The adult breathing rate distribution has a mean, standard deviation, median and 95th percentile of 232, 64.6, 209, and 381 L/kg-day, respectively. The simulated 70-year distribution has a mean, standard deviation, median and 95th percentile of 271, 57.9, 253, and 393 L/kg-day, respectively. The adult breathing rate distribution is based on 24-hour recall activity data that would not necessarily capture average activity patterns and therefore breathing rates. We utilized the human energy expenditure literature to validate the breathing rate distribution. We conclude that the breathing rate distribution is reasonable for chronic long-term risk assessment in Californias Air Toxics Hot Spots program.

Inhalation of an essential metal: development of reference exposure levels for manganese.

Exposures to high levels of manganese by ingestion or inhalation can damage the central nervous system. However, the capacity of environmental manganese to cause neurotoxicity is of most concern following inhalation exposure. Reference exposure levels (RELs) are values developed by California EPAs Office of Environmental Health Hazard Assessment (OEHHA) to protect the general public from periodic and continual exposures to airborne toxicants. The recently revised guidelines for the development of noncancer RELs encourage the use of benchmark dose methodology where appropriate, and explicitly address the potential susceptibilities associated with early-life exposures (OEHHA, 2008). This paper describes the application of those guidelines to the derivation of RELs to protect the general public from routine 8h and chronic exposures to airborne manganese. The data were amenable to benchmark analysis and the RELs derived reflect the mounting evidence that children represent a population that is differentially susceptible to manganese toxicity.

Using ToxCast to Explore Chemical Activities and Hazard Traits: A Case Study With Ortho-Phthalates

US EPAs Toxicity Forecaster (ToxCastTM) is a tool with potential use in evaluating safer consumer products, conducting chemical alternatives analyses, prioritizing chemicals for exposure monitoring, and ultimately performing screening-level risk assessments. As a case study exploring a potential use of ToxCast, we evaluated ToxCast results for ortho-phthalates focused on the well-established toxicological endpoints of some members of this class. We compared molecular perturbations measured in ToxCast assays with the known apical toxicity endpoints of o-phthalates reported in the open literature to broadly reflect on the predictive capability of the high-throughput screening (HTS) assays. We grouped the ToxCast assays into defined sets to examine o-phthalate activity and potency. This study revealed several links between key molecular events assayed in vitro and chemical-specific hazard traits. In general, parent o-phthalates are more active than their monoester metabolites. The medium-chain length o-phthalate group is also more active than other o-phthalate groups, as supported by Toxicological Priority Index ranking and statistical methods. Some HTS assay results correlated with in vivo findings, but others did not. For example, there was a notable lack of assay activity to explain the known male reproductive toxicity of these compounds. Ultimately, HTS data resources such as ToxCast may inform us of sensitive upstream toxicity endpoints and may assist in the rapid identification of environmental chemical hazards for screening and prioritization. However, this case study shows that the absence of positive results in ToxCast in vitro assays cannot be interpreted as absence of related in vivo toxicity, and limited biological coverage by the assays remains a concern.

Volatile Organic Compounds from Pesticide Application and Contribution to Tropospheric Ozone

Publisher Summary Volatile organic compounds (VOC) are organic chemicals that when released into the atmosphere can react with sunlight and nitrogen oxides (NOx) to form tropospheric (ground-level) ozone. Two general classes of pesticide products contribute the vast majority of pesticidal VOC emissions: fumigants and emulsifiable concentrates (EC). The relatively widespread use, high application rates, and high volatility underlie the large contribution of fumigants to the VOC problem from pesticide applications. At high concentrations, tropospheric ozone (O 3 ) causes respiratory problems and is detrimental to a wide variety of plants. Under normal (unpolluted) conditions, O 3 concentrations are relatively low because reaction prevents any buildup of O 3 . However, when reactive VOCs are present, they can photolyze to form radicals that react with NO. The primary target organ for O 3 health effects is the respiratory organs. O 3 induces lipid peroxidation, a free radical chain reaction involving membrane lipids. Ozone can act to exacerbate asthma and may be involved in induction of asthma in children. Recent studies implicate ozone in mortality from exacerbation of cardiovascular and pulmonary disease. Thus, control of tropospheric ozone is a major concern of regulatory agencies. Reduction of reactive VOC components of pesticide applications is important for the control of ozone in agricultural areas.