Potential impacts of synthetic food dyes on activity and attention in children: a review of the human and animal evidence.

Concern that synthetic food dyes may impact behavior in children prompted a review by the California Office of Environmental Health Hazard Assessment (OEHHA). OEHHA conducted a systematic review of the epidemiologic research on synthetic food dyes and neurobehavioral outcomes in children with or without identified behavioral disorders (particularly attention and activity). We also conducted a search of the animal toxicology literature to identify studies of neurobehavioral effects in laboratory animals exposed to synthetic food dyes. Finally, we conducted a hazard characterization of the potential neurobehavioral impacts of food dye consumption. We identified 27 clinical trials of children exposed to synthetic food dyes in this review, of which 25 were challenge studies. All studies used a cross-over design and most were double blinded and the cross-over design was randomized. Sixteen (64%) out of 25 challenge studies identified some evidence of a positive association, and in 13 (52%) the association was statistically significant. These studies support a relationship between food dye exposure and adverse behavioral outcomes in children. Animal toxicology literature provides additional support for effects on behavior. Together, the human clinical trials and animal toxicology literature support an association between synthetic food dyes and behavioral impacts in children. The current Food and Drug Administration (FDA) acceptable daily intakes are based on older studies that were not designed to assess the types of behavioral effects observed in children. For four dyes where adequate dose-response data from animal and human studies were available, comparisons of the effective doses in studies that measured behavioral or brain effects following exposure to synthetic food dyes indicate that the basis of the ADIs may not be adequate to protect neurobehavior in susceptible children. There is a need to re-evaluate exposure in children and for additional research to provide a more complete database for establishing ADIs protective of neurobehavioral effects.

Using High-Throughput Screening to Evaluate Perturbations Potentially Linked to Neurobehavioral Outcomes: A Case Study Using Publicly Available Tools on FDA Batch-Certified Synthetic Food Dyes.

There is growing evidence from human and animal studies indicating an association between exposure to synthetic food dyes and adverse neurobehavioral outcomes in children. However, data gaps persist for potential mechanisms by which the synthetic food dyes could elicit neurobehavioral impacts. We developed an approach to evaluate seven US FDA-batch-certified food dyes using publicly available high-throughput screening (HTS) data from the US EPA's Toxicity Forecaster to assess potential underlying molecular mechanisms that may be linked to neurological pathway perturbations. The dyes were screened through 270 assays identified based on whether they had a neurological-related gene target and/or were mapped to neurodevelopmental processes or neurobehavioral outcomes, and were conducted in brain tissue, targeted specific hormone receptors, or targeted oxidative stress and inflammation. Some results provided support for neurological impacts found in human and animal studies, while other results showed a lack of correlation with in vivo findings. The azo dyes had a range of activity in assays mapped to G-protein-coupled receptors and were active in assays targeting dopaminergic, serotonergic, and opioid receptors. Assays mapped to nuclear receptors (androgen, estrogen, and thyroid hormone) also exhibited activity with the food dyes. Other molecular targets included the aryl hydrocarbon receptor, acetylcholinesterase, and monoamine oxidase. The Toxicological Prioritization Index tool was used to visualize the results of the Novascreen assays. Our results highlight certain limitations of HTS assays but provide insight into potential underlying mechanisms of neurobehavioral effects observed in in vivo animal toxicology studies and human clinical studies.

Healthy Air, Healthy Brains: Advancing Air Pollution Policy to Protect Children's Health.

Evidence is growing on the adverse neurodevelopmental effects of exposure to combustion-related air pollution. Project TENDR (Targeting Environmental Neurodevelopmental Risks), a unique collaboration of leading scientists, health professionals, and children's and environmental health advocates, has identified combustion-related air pollutants as critical targets for action to protect healthy brain development. We present policy recommendations for maintaining and strengthening federal environmental health protections, advancing state and local actions, and supporting scientific research to inform effective strategies for reducing children's exposures to combustion-related air pollution. Such actions not only would improve children's neurological development but also would have the important co-benefit of climate change mitigation and further improvements in other health conditions.

Exposures to FD&C synthetic color additives from over-the-counter medications and vitamins in United States children and pregnant women.

BACKGROUND: Food and Drug Administration (FDA) Food Drug and Cosmetic (FD&C) synthetic color additives (SCAs) have been associated with attentional and behavioral problems in children. Efforts to quantify exposure have focused on foods, while the contribution of medications and supplements remains unknown. OBJECTIVE: To estimate exposures to SCAs in children (2-16 years) and pregnant women from intake of common over-the-counter (OTC) medications and vitamins. METHODS: We estimated single-day exposure (mg/kg/day) to FD&C SCAs based on measurements of 25 different products and recommended dosages on product labels. Exposures were compared to SCA exposure estimates from food we previously developed and acceptable daily intakes (ADIs) established by FDA and the World Health Organization. RESULTS: The highest exposure was found for FD&C Red No. 40 in a children's cold/cough/allergy syrup. A child aged 12-16 years consuming the maximum daily dosage would have an exposure of 0.221 mg/kg/day, which is twice this age group's typical exposure to this additive from food. No estimated exposures exceeded the ADIs. SIGNIFICANCE: Some children's OTC medications and vitamins may cause daily SCA exposures comparable to those from foods. OTC medications and vitamins should be considered in efforts to quantify population exposure to FD&C SCAs. IMPACT: Exposure to synthetic color additives (SCAs) from foods has been associated with behavioral problems in children. Exposures from over-the-counter (OTC) medications and vitamins remain unquantified despite widespread use. We estimated exposures in children and pregnant women for 25 different OTC medication and vitamin products sold in the United States. While exposures were below acceptable daily intakes (ADIs) established by the US Food and Drug Administration and the World Health Organization, some were comparable to typical daily exposures from foods. This work critically informs future SCA exposure assessments and provides valuable information for parents concerned about the health effects of SCAs.

Dietary Exposure to United States Food and Drug Administration-Approved Synthetic Food Colors in Children, Pregnant Women, and Women of Childbearing Age Living in the United States.

The Food and Drug Administration (FDA) regulates artificial food colors (AFCs) in the United States. Exposure to AFCs has raised concerns about adverse behavioral effects in children. We quantified AFC exposure in women of childbearing age, pregnant women, and children and compared them to FDA and World Health Organization acceptable daily intakes (ADIs). We estimated the "typical" and "high" single-day and two-day average dietary exposure to each AFC (mg/kg/day) based on laboratory measurements and food consumption data from the 2015−2016 National Health and Nutrition Examination Survey (NHANES). We also examined whether AFC intake differed by income, education, and ethnicity. Exposure tended to be higher in children and the highest AFC exposure was found for Red No. 40. Children's mean and 95th percentile FD&C Red No. 3 estimated intakes exceeded the ADIs in some instances. Juice drinks, soft drinks, icings, and ice cream cones were major foods contributing to children's (<16 years old) AFC exposure. AFC intake was higher in participants with lower incomes and education and of African American ethnicity. The findings indicate widespread AFC exposure including in very young children. Research is needed on the sociodemographic determinants of exposure and AFC toxicokinetics to better describe the absorption and organ-specific exposure.

Ethylmalonic encephalopathy masquerading as meningococcemia.

Ethylmalonic encephalopathy (MIM #602473) is a rare autosomal recessive metabolic condition caused by biallelic variants in ETHE1 (MIM #608451), characterized by global developmental delay, infantile hypotonia, seizures, and microvascular damage. The microvascular changes result in a pattern of relapsing spontaneous diffuse petechiae and purpura, positional acrocyanosis, and pedal edema, hemorrhagic suffusions of mucous membranes, and chronic diarrhea. Here, we describe an instructive case in which ethylmalonic encephalopathy masqueraded as meningococcal septicemia and shock. Ultrarapid whole-genome testing (time to result 60 h) and prompt biochemical analysis facilitated accurate diagnosis and counseling with rapid implementation of precision treatment for the metabolic crisis related to this condition. This case provides a timely reminder to consider rare genetic diagnoses when atypical features of more common conditions are present, with an early referral to ensure prompt biochemical and genomic diagnosis.

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 EPA's 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.

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.

Dig deeper when it does not make sense: Juvenile xanthomas due to sitosterolemia.

Sitosterolemia is an extremely rare autosomal recessive disease caused by mutations in either ABCG5 or ABCG8, which encode for a sterol efflux transporter (sterolin) that pumps sterols out into the intestinal lumen or into bile. This leads to progressive accumulation of plant sterols in blood and tissues. Clinical presentation is variable and may include xanthoma, arthritis, thyroid dysfunction, premature atherosclerotic disease, splenomegaly, and hematologic manifestations. We report a child presented with multiple xanthomas at age 5.5 years, located on the elbow, knee, and toe. Juvenile xanthogranuloma was considered based on histopathologic findings. At 8 years of age, a lipid profile showed markedly elevated total cholesterol (9.4 mmol/L) and low-density lipoprotein cholesterol (LDL-C, 7.4 mmol/L). Simvastatin therapy was initiated, however, the lipid profile was persistently abnormal. At age 8.5 years, genetic testing identified two novel variants: (NM_022437.3[ABCG8]:c.1444del;p.Leu482Trpfs*40) and (NM_022437.3[ABCG8]:c.1640T>C;p.Leu547Pro) in the ABCG8 gene. Plasma sitosterol was subsequently found to be very high, confirming the diagnosis. She was started on a low plant sterol and cholesterol diet for 6 weeks with insignificant response and therefore ezetimibe (10 mg daily) was added. This resulted in significant reduction of cholesterol, LDL, sitosterol levels, and no further increase in the size of the xanthomas. This case emphasizes the diagnostic odyssey, the benefits of genomic testing and importance of a correct diagnosis in order to initiate appropriate therapy. It also illustrates the importance of considering rare conditions, such as sitosterolemia, as a differential diagnosis in patients with hypercholesterolemia and increased LDL-C.

An Integrated Approach Using Publicly Available Resources for Identifying and Characterizing Chemicals of Potential Toxicity Concern: Proof-of-Concept With Chemicals That Affect Cancer Pathways.

We developed an integrated, modular approach to predicting chemical toxicity relying on in vitro assay data, linkage of molecular targets to disease categories, and software for ranking chemical activity and examining structural features (chemotypes). We evaluate our approach in a proof-of-concept exercise to identify and prioritize chemicals of potential carcinogenicity concern. We identified 137 cancer pathway-related assays from a subset of U.S. EPA's ToxCast platforms. We mapped these assays to key characteristics of carcinogens and found they collectively assess 5 of 10 characteristics. We ranked all 1061 chemicals screened in Phases I and II of ToxCast by their activity in the selected cancer pathway-related assays using Toxicological Prioritization Index software. More chemicals used as biologically active agents (eg, pharmaceuticals) ranked in the upper 50% versus lower 50%. Twenty-three chemotypes are enriched in the top 5% (n = 54) of chemicals; these features may be important for their activity in cancer pathway-related assays. The biological coverage of the ToxCast assays related to cancer pathways is limited and short-term assays may not capture the biology of some key characteristics. Metabolism is also minimal in the assays. The ability of our approach to identify chemicals with cancer hazard is limited with the current input data, but we expect that our approach can be applied with future iterations of ToxCast and other data for improved chemical prioritization and characterization. The novel approach and proof-of-concept exercise described here for ranking chemicals for potential carcinogenicity concern is modular, adaptable, and amenable to evolving data streams.

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.

Children's Environmental Health: Beyond National Boundaries.

Children are especially vulnerable to environmental pollution, a major cause of disease, death, and disability in countries at every level of development. This article reviews threats to children, including air and water pollution, toxic industrial chemicals, pesticides, heavy metals, and hazardous wastes. Global climate change is expected to exacerbate many of these issues. Examples of innovative nongovernmental organizations and governmental programs that address the impacts of environmental hazards on children are included. International travel, adoption, migration, and movement of goods and pollutants worldwide make these conditions concerns for all pediatricians.

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

US EPA's 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.

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.

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 microm 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.

The association between exposure to environmental tobacco smoke and breast cancer: a review by the California Environmental Protection Agency.

BACKGROUND: The California Environmental Protection Agency (Cal/EPA) recently completed a health effects assessment of exposure to environmental tobacco smoke (ETS) which resulted in California listing ETS as a Toxic Air Contaminant in January 2006. As part of the assessment, studies on the association between exposure to ETS and breast cancer were reviewed. METHODS: Twenty-six published reports (including 3 meta-analyses) evaluating the association between ETS exposure and breast cancer were reviewed. A weight-of-evidence approach was applied to evaluate the data and draw conclusions about the association between breast cancer and ETS exposure. RESULTS: The published data indicate an association between ETS and breast cancer in younger primarily premenopausal women. Thirteen of 14 studies (10 case-control and four cohort) that allowed analysis by menopausal status reported elevated risk estimates for breast cancer in premenopausal women, seven of which were statistically significant. Our meta-analyses indicated elevated summary relative risks ranging from OR 1.68 (95% C.I. 1.31, 2.15) for all 14 studies to 2.20 (95% C.I. 1.69, 2.87) for those with the best exposure assessment. CONCLUSIONS: Cal/EPA concluded that regular ETS exposure is causally related to breast cancer diagnosed in younger, primarily premenopausal women and that the association is not likely explained by bias or confounding.

Development of a chronic inhalation reference level for respirable crystalline silica.

Chronic inhalation exposure of workers to crystalline silica can result in silicosis. The general public can also be exposed to lower levels of crystalline silica from quarries, sand blasting, and entrained fines particles from surface soil. We have derived an inhalation chronic reference exposure level for silica, a level below which no adverse effects due to prolonged exposure would be expected in the general public. Incidence of silicosis and silica exposure data from a cohort of 2235 white South African gold miners yielded a reference level of 3 microg/m3) for respirable silica (particle size as defined occupationally) using a benchmark concentration approach. Data from cohorts of American gold miners, Chinese tin miners, diatomaceous earth workers, and black South African gold miners yielded similar results with a range of 3-10 microg/m3. Strengths of the chronic reference exposure level include the availability of several large long-term studies of inhalation in workers at varying exposure concentrations, adequate histopathological and radiologic analysis, adequate follow-up of exposed workers, a dose-response effect in several studies, observation of a No Observed Adverse Effect Level in the key study, and the power of the key study to detect a small effect. Uncertainties include the general underestimation of silicosis by radiography alone and the uncertainties in exposure estimation.