Exploring the utility of the Threshold of Toxicological Concern (TTC) as a screening approach for complex substances.

The Threshold of Toxicological Concern (TTC) has been applied to assess chemical safety for use, particularly in the food safety area. Although the TTC was developed for application to an individual chemical structure, more recently this concept has been suggested for the assessment of combined exposures to multiple chemicals. This study evaluated the potential for applying the TTC to a specific type of co-exposure, that of a complex substance of variable composition which contains multiple constituents, following the World Health Organization/International Programme on Chemical Safety framework for risk assessment of combined exposure to multiple chemicals. The results indicated that the TTC threshold was lower (i.e., more conservative) than regulatory thresholds derived for the same substance or even its most toxic constituent, providing assurance that the TTC could meet the requirements for a conservative screening process. This case study indicates that the TTC concept can be a useful tool to screen for potential risks from complex substances, with the consideration of additional aspects such as variability in chemical constituents and their relative proportions within the substance.

Comparisons of PNEC derivation logic flows under example regulatory schemes and implications for ecoTTC.

Derivation of Predicted No Effect Concentrations (PNECs) for aquatic systems is the primary deterministic form of hazard extrapolation used in environmental risk assessment. Depending on the data availability, different regulatory jurisdictions apply application factors (AFs) to the most sensitive measured endpoint to derive the PNEC for a chemical. To assess differences in estimated PNEC values, two PNEC determination methodologies were applied to a curated public database using the EnviroTox Platform (www.EnviroToxdatabase.org). PNECs were derived for 3647 compounds using derivation procedures based on example US EPA and a modified European Union chemical registration procedure to allow for comparisons. Ranked probability distributions of PNEC values were developed and 5th percentile values were calculated for the entire dataset and scenarios where full acute or full chronic data sets were available. The lowest PNEC values indicated categorization based on chemical attributes and modes of action would lead to improved extrapolations. Full acute or chronic datasets gave measurably higher 5th percentile PNEC values. Algae were under-represented in available ecotoxicity data but drove PNECs disproportionately. Including algal inhibition studies will be important in understanding chemical hazards. The PNEC derivation logic flows are embedded in the EnviroTox Platform providing transparent and consistent PNEC derivations and PNEC distribution calculations.

Twin Births in Medicaid: Prevalence, Outcomes, Utilization, and Cost in Four States, 2014-2015.

OBJECTIVES: Twin births have increased in prevalence. Twin births are more likely to have poorer outcomes than singleton births and are more costly. However, although Medicaid paid for approximately half of U.S. births in 2016, little is known specifically about the incidence of twin births and related costs for Medicaid beneficiaries. This paper seeks to expand the knowledge of twin births covered by Medicaid. METHODS: We obtained data for singleton (N = 115,568) and twin (N = 3775) Medicaid-covered births in selected geographic areas of four states in 2014 and 2015. States provided linked birth certificates to Medicaid claims data for mothers and infants. We compared health care utilization and Medicaid costs for twins to singletons in the same geographic areas. RESULTS: The prevalence of Medicaid twins in the selected areas of these four states was 3.2% of births, identical to the rate of twins nationwide. Two thirds of Medicaid twins were born preterm, and average gestational age was 34.8 weeks. Mothers of twins had higher rates of C-Sect. (73.6% vs. 32.0% for singletons) and of neonatal intensive care use (45.2% vs. 11.1%). The average length of delivery stay for twins was 12.3 days, vs. 4.1, and the rate of hospital readmissions was almost twice as high. The total cost for mother and infant over the prenatal, delivery, and post-natal period for a pair of twins was $48,479, over two and a half times as high as for singleton births ($18,032). However, when considering the average cost of a single twin vs. a singleton birth, the cost differential is less ($24,239 vs. $18,032, or a ratio of 1.34). CONCLUSIONS: Medicaid twins are a fragile population with poorer outcomes and higher service use than singleton infants. Twins contribute substantially to the Medicaid cost of maternity and newborn care. A variety of strategies can be used to improve twin outcomes and reduce costs.

Community-based directly observed treatment for TB patients to improve HIV services: a cross-sectional study in a South African province.

BACKGROUND: There is uncertainty about how directly observed treatment (DOT) support for tuberculosis (TB) can be delivered most effectively and how DOT support can simultaneously be used to strengthen human immunodeficiency virus (HIV) prevention and control among TB patients. This study describes how DOT support by community health workers (CHWs) was used in four municipalities in the Free State province - a high TB/HIV burden, poorly-resourced setting - to provide HIV outreach, referrals, and health education for TB patients. METHODS: The study was part of a larger cross-sectional study of HIV counselling and testing (HCT) among 1101 randomly-selected TB patients registered at 40 primary health care (PHC) facilities (clinics and community health centres) across small town/rural and large town/urban settings. Univariate analysis of percentages, chi-square tests and t-tests for difference in means were used to describe differences between the types of TB treatment support and patient characteristics, as well as the types of - and patient satisfaction with - HIV information and referrals received from various types of treatment supporters including home-based DOT supporters, clinic-based DOT supporters or support from family/friends/employers. Multivariate logistic regression was used to predict the likelihood of not having receiving home-based DOT and of never having received HIV counselling. The independent variables include poverty-related health and socio-economic risk factors for poor outcomes. Statistical significance is shown using a 95% confidence interval and a 0.05 p-value. RESULTS: Despite the fact that DOT support for all TB patients was the goal of South African health policy at the time (2012), most TB patients were not receiving formal DOT support. Only 155 (14.1%) were receiving home-based DOT, while 114 (10.4%) received clinic-based DOT. TB patients receiving home-based DOT reported higher rates of HIV counselling than other patients. CONCLUSIONS: Public health providers should train DOT supporters to provide HIV prevention and target DOT to those at greatest risk of HIV, particularly those at greatest socio-economic risk.

Son Preference of Immigrants to the United States: Data from U.S. Birth Certificates, 2004-2013.

Son preference has existed for centuries in many cultures and societies. In some Asian countries, including China and India, the sex ratio at birth (SRB, number of male infants divided by number of female infants times 100) is elevated above the worldwide biological norm of about 105. We investigate whether this ratio is elevated in the U.S. for immigrant women. We analyze U.S. birth certificates for 2004-2013 and categorize births by mother's and father's race/ethnicity; mother's place of birth, and birth order of the child. The SRB is elevated for two groups of women: Chinese women born in China for children of birth order 2 and higher, and Indian women born in India for children of birth order 3 and higher. The SRB is not elevated for Chinese and Indian women born in the U.S., nor for Mexican women, Black women, nor White women, regardless of place of birth. The race/ethnicity of the child's father does not appear to be a strong factor in the SRB. In the early twenty-first century the elevated SRB for Chinese and Indian women born in China and India respectively suggests sex selection for higher order births in the U.S.

Validation of the 8th Edition of the AJCC TNM Staging System for Gastric Cancer using the National Cancer Database.

BACKGROUND: The 8th edition AJCC gastric cancer staging manual was refined using Japanese and Korean data from the International Gastric Cancer Association (IGCA). This study evaluated the eighth edition's validity for U.S. METHODS: National Cancer Database (NCDB) was used to obtain data on gastric cancer patients diagnosed from 2004 to 2008 who underwent surgery and to examine differences in stage grouping and survival between AJCC 7th and 8th editions. Discrimination of models derived from NCDB and IGCA data was compared. RESULTS: Of 12,041 patients, median age was 65, 57.6% were male, median lymph nodes retrieved was 2 (0-76), 30.9% underwent distal/partial gastrectomy, and 49.8% received no adjuvant treatment. The 8th edition differed in that T1-T3 disease was upstaged with N3b, T4aN3a was downstaged from IIIC to IIIB, and T4bN0 and T4aN2 were downstaged from IIIB to IIIA. These changes resulted in increased patients in IIIA (1436 in the 7th edition to 2310 in the 8th) and IIIB (1737-1896) and decreased in IIIC (2100-1067). This also resulted in lower median survival for IIIA (28.7-25.0 months), IIIB (19.6-17.4), IIIC (13.7-11.8). The concordance index for the 8th edition applied to NCDB data was 0.719 [95% confidence interval (CI) 0.703-0.734), which is comparable to that for the 8th edition developed from IGCA data (0.775, 95% CI 0.770-0.780) and the 7th edition applied to NCDB data (0.720, 95% CI 0.704-0.735). CONCLUSIONS: The 8th edition is valid for U.S. populations, showing clear separation of data with preservation of group order.

Mode of Action (MOA) Assignment Classifications for Ecotoxicology: An Evaluation of Approaches.

The mode of toxic action (MOA) is recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, MOA classification has never been standardized in ecotoxicology, and a comprehensive comparison of classification tools and approaches has never been reported. Here we critically evaluate three MOA classification methodologies using an aquatic toxicity data set of 3448 chemicals, compare the approaches, and assess utility and limitations in screening and early tier assessments. The comparisons focused on three commonly used tools: Verhaar prediction of toxicity MOA, the U.S. Environmental Protection Agency (EPA) ASsessment Tool for Evaluating Risk (ASTER) QSAR (quantitative structure activity relationship) application, and the EPA Mode of Action and Toxicity (MOAtox) database. Of the 3448 MOAs predicted using the Verhaar scheme, 1165 were classified by ASTER, and 802 were available in MOAtox. Of the subset of 432 chemicals with MOA assignments for each of the three schemes, 42% had complete concordance in MOA classification, and there was no agreement for 7% of the chemicals. The research shows the potential for large differences in MOA classification between the five broad groups of the Verhaar scheme and the more mechanism-based assignments of ASTER and MOAtox. Harmonization of classification schemes is needed to use MOA classification in chemical hazard and risk assessment more broadly.

Emergency department use by centenarians: the 2008 Nationwide Emergency Department Sample.

INTRODUCTION: Older adults have higher rates of emergency department use than do younger adults, and the number of centenarians is expected to increase. The objective of this study was to examine centenarians' use of the emergency department in the United States, including diagnoses, charges, and disposition. METHODS: The 2008 Nationwide Emergency Department Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality provided encounter-level data on emergency department visits and weights for producing nationwide estimates. From this data set, we collected patient characteristics including age, sex, primary diagnosis, and disposition. We used χ(2) tests and t tests to test for significant differences among people aged 80 to 89, 90 to 99, and 100 years or older. RESULTS: Centenarians had a lower rate of emergency department use than those aged 90 to 99 (736 per 1,000 vs 950 per 1,000; P < .05). We found no significant difference in use between centenarians and those aged 80 to 89. The most common diagnoses for centenarians were superficial injuries (5.8% of visits), pneumonia (5.1%), and urinary tract infections (5.1%). Centenarians were more likely to visit the emergency department for fall-related injuries (21.5%) than those aged 80 to 89 (14.1%; P < .05) and 90 to 99 (18.7%; P < .05). Centenarians were more likely to die in the emergency department (2.0%) than were those aged 80 to 89 (0.6%; P < .05) and 90 to 99 (0.7%; P < .05). CONCLUSION: Centenarians in emergency departments in the United States have different diagnoses, conditions, and outcomes than other older Americans.

Alternatives to in vivo tests to detect endocrine disrupting chemicals (EDCs) in fish and amphibians--screening for estrogen, androgen and thyroid hormone disruption.

Endocrine disruption is considered a highly relevant hazard for environmental risk assessment of chemicals, plant protection products, biocides and pharmaceuticals. Therefore, screening tests with a focus on interference with estrogen, androgen, and thyroid hormone pathways in fish and amphibians have been developed. However, they use a large number of animals and short-term alternatives to animal tests would be advantageous. Therefore, the status of alternative assays for endocrine disruption in fish and frogs was assessed by a detailed literature analysis. The aim was to (i) determine the strengths and limitations of alternative assays and (ii) present conclusions regarding chemical specificity, sensitivity, and correlation with in vivo data. Data from 1995 to present were collected related to the detection/testing of estrogen-, androgen-, and thyroid-active chemicals in the following test systems: cell lines, primary cells, fish/frog embryos, yeast and cell-free systems. The review shows that the majority of alternative assays measure effects directly mediated by receptor binding or resulting from interference with hormone synthesis. Other mechanisms were rarely analysed. A database was established and used for a quantitative and comparative analysis. For example, a high correlation was observed between cell-free ligand binding and cell-based reporter cell assays, between fish and frog estrogenic data and between fish embryo tests and in vivo reproductive effects. It was concluded that there is a need for a more systematic study of the predictive capacity of alternative tests and ways to reduce inter- and intra-assay variability.

The impact of the Medicaid/CHIP expansions on children: a synthesis of the evidence.

This article reviews findings from 38 rigorous studies published in the peer-reviewed literature of the impact of the Medicaid/Children's Health Insurance Program (CHIP) expansions on children. There is strong evidence for increases in enrollment in public programs and reductions in uninsurance following eligibility expansions. Medicaid enrollment continued to increase during the CHIP era (a "spillover effect"). Evidence for improved access to and use of services, particularly for dental care, is also very strong. There are fewer studies of health status impacts, and the evidence is mixed. There is a very wide range in the size of effects estimated in the studies reviewed because of the methods used and the populations studied. The review identifies several important research gaps on this topic, particularly the small number of studies of the effects on health status. Both research methods and findings from the child expansions can provide insights for evaluating the coming expansions for adults under the Affordable Care Act.

An evaluation of a chronic disease prevention program in the Republika Srpska (RS) of Bosnia and Herzegovina.

INTRODUCTION: In 2002 the Republika Srpska of Bosnia and Herzegovina adopted goals for reducing the burden of chronic disease through a new screening program in its publicly funded health centers ("Dom Zdravljas"). This study evaluated the first year of program implementation. METHODS: The evaluation used in-depth interviews with 25 key stakeholders and in-person interviews with 1004 citizens. RESULTS: We found that many health care providers and citizens were unaware of the program. In addition, there was inadequate financing for the program, because the Health Insurance Fund does not collect revenue for uninsured citizens, more than 20 per cent of the population. CONCLUSION: We recommend improved co-ordination among public and private organizations involved in implementation; increased promotion of the program with health care providers and citizens; and increased financial resources for providing screening for uninsured citizens.

Improving coverage and access for immigrant Latino children: the Los Angeles healthy kids program.

A large number of California counties have recently taken bold steps to extend health insurance to all poor and near-poor children through county-based Children's Health Initiatives. One initiative, the Los Angeles Healthy Kids program, extends coverage to uninsured children in families with incomes below 300 percent of the federal poverty level who are ineligible for Medi-Cal (California Medicaid) and Healthy Families (its State Children's Health Insurance Program). A four-year evaluation of Healthy Kids finds that the program has improved access for more than 40,000, most of whom are immigrant Latino children, who have almost no access to employer coverage. However, sustaining this effective program has proved to be challenging.

Variations in medicaid mental health service use and cost for children.

Mental health care is a critical component of Medicaid for children. This study used summary tables drawn from the 1999 Medicaid Analytic Extract (MAX) files, the first available Medicaid data for the entire US, to examine fee-for-service Medicaid in 23 selected states. Data show that 9% of children and youth (ages 0-21) had a mental health-related diagnosis on a claim, varying from 5% to 17% across the states. The proportion increased with age, and was higher for boys. Over half of those diagnosed received psychotropic medication, and approximately 7% had an inpatient psychiatric admission during the year. Mental health costs accounted for 26.5% of total fee-for-service Medicaid expenditures, varying from 14% to 61% depending on the state.

The effect of new insurance coverage on the health status of low-income children in Santa Clara County.

OBJECTIVE: To examine whether providing health insurance coverage to undocumented children affects the health of those children. DATA SOURCES/STUDY SETTING: The data come from a survey of 1235 parents of enrollees in the new insurance program ("Healthy Kids") in Santa Clara County, California. The survey was conducted from August 2003 to July 2004. STUDY DESIGN: Cross-sectional study using a group of children insured for one year as the study group (N=626) and a group of newly insured children as the comparison group (N=609). Regression analysis is used to adjust for differences in the groups according to a range of characteristics. DATA COLLECTION: Parents were interviewed by telephone in either English or Spanish (most responded in Spanish). The response rate was 89 percent. PRINCIPAL FINDINGS: The study group-who were children continuously insured by Healthy Kids for one year-were significantly less likely to be in fair/poor health and to have functional impairments than the comparison group of newly insured children (15.9 percent versus 28.5 percent and 4.5 percent versus 8.4 percent, respectively). Impacts were largest among children who enrolled for a specific medical reason (such as an illness or injury); indeed, the impact on functional limitations was evident only for this subgroup. The study group also had fewer missed school days than the comparison group, but the difference was significant only among children who did not enroll for a medical reason. CONCLUSIONS: Health insurance coverage of undocumented children in Santa Clara County was associated with significant improvements in children's health status. The size of this association could be overstated, since the comparison sample included some children who enrolled because of an illness or other temporary health problem that would have improved even without insurance coverage. However, even after limiting the study sample to children who did not enroll for a medical reason, a significant association remained between children's reported health and their health coverage. We thus cautiously conclude that Healthy Kids had a favorable impact on children's health.

A tale of two counties: expanding health insurance coverage for children in California.

During difficult economic times, many California counties have expanded health insurance coverage for low-income children. These Children's Health Initiatives (CHIs) enroll children in public programs and provide new health insurance, Healthy Kids, for those ineligible for existing programs. This article describes the policy issues in implementing the Santa Clara and San Mateo County CHIs, as well as the children's enrollment levels and utilization of services. These CHIs are among the first of the thirty California counties planning or implementing such initiatives. Their success depends on leadership from county agencies that have not traditionally worked closely together, as well as the development of a diverse public and private funding base. This effort to provide universal coverage for all children is important to national policymakers desiring similar goals.

Lack of p53 induction in fish cells by model chemotherapeutics.

Although p53 has been extensively studied in mammalian models, relatively little is known about its specific function in lower vertebrates. It has long been assumed that p53 pathways characterized in mammals apply to other vertebrates as well. Fish provide a useful model for the study of environmental carcinogenesis, and populations of fish inhabiting highly polluted environments provide information on the etiology of pollutant-mediated cancer. In this study, we investigated p53 protein and apoptosis induction in PLHC-1 (desert topminnow hepatocellular carcinoma), RTL-W1 (rainbow trout normal liver), and primary rainbow trout hepatocytes exposed to model chemotherapeutics. All of the chemicals used in these studies have been demonstrated to increase p53 protein levels and induce apoptosis in mammalian cell lines. In contrast, PLHC-1 p53 protein was not induced in response to any model mammalian p53 inducers following 24 h exposures. Additionally, both trout cell types demonstrated this same lack of p53 induction upon exposure to model chemotherapeutic drugs. PLHC-1 cells demonstrated an induction of apoptosis as measured by caspase-3 activation following exposure to all of the chemotherapeutics tested. Our results suggest that fish p53 may be activated differently from that of their mammalian counterparts, and that important differences may exist between phyla in the function and regulation of p53 as well as other mechanisms involved in environmental carcinogenesis.

Trends in maternal and infant health in poor urban neighborhoods: good news from the 1990s, but challenges remain.

OBJECTIVES: During the 1990s, numerous public policy changes occurred that may have affected the health of mothers and infants in low-income neighborhoods. This article examines trends in key maternal and child health indicators to determine whether disparities between high-poverty neighborhoods and other neighborhoods have declined. METHODS: Using neighborhood-level vital statistics and U.S. Census data, we categorized "neighborhoods" (Census tracts) as being high poverty (greater than 30% of population below the federal poverty level in 1990) or not. We compared trends in four key indicators--births to teenagers, late prenatal care, low birth-weight; and infant mortality--over the 1990s among high-poverty and other neighborhoods in Cuyahoga County, Ohio; Denver, Colorado; Marion County, Indiana; and Oakland, California. RESULTS: In all four metropolitan areas, trends in high-poverty neighborhoods were more favorable than in other neighborhoods. The most consistently positive trend was the reduction in the rate of teen births. The metropolitan areas with the most intensive programs to improve maternal and child health--Cuyahoga County and Oakland-saw the most consistent improvement across all indicators. Still, great disparities between high-poverty and other neighborhoods remain, and only Oakland shows promise of achieving some of the Healthy People 2010 maternal and child health goals in its high-poverty neighborhoods. CONCLUSIONS: While there has been a reduction in maternal and infant health disparities between high-poverty and other neighborhoods, much work remains to eliminate disparities and achieve the 2010 goals. Small area data are useful in isolating the neighborhoods that should be targeted. Experience from the 1990s suggests that a combination of several intensive interventions can be effective at reducing disparities.

The impact of Medicaid managed care on pregnant women in Ohio: a cohort analysis.

OBJECTIVE: To examine the impact of mandatory HMO enrollment for Medicaid-covered pregnant women on prenatal care use, smoking, Cesarean section (C-section) use, and birth weight. DATA SOURCES/STUDY SETTING: Linked birth certificate and Medicaid enrollment data from July 1993 to June 1998 in 10 Ohio counties, 6 that implemented mandatory HMO enrollment, and 4 with low levels of voluntary enrollment (under 15 percent). Cuyahoga County (Cleveland) is analyzed separately; the other mandatory counties and the voluntary counties are grouped for analysis, due to small sample sizes. Study Design. Women serve as their own controls, which helps to overcome the bias from unmeasured variables such as health beliefs and behavior. Changes in key outcomes between the first and second birth are compared between women who reside in mandatory HMO enrollment counties and those in voluntary enrollment counties. County of residence is the primary indicator of managed care status, since, in Ohio, women are allowed to "opt out" of HMO enrollment in mandatory counties in certain circumstances, leading to selection. As a secondary analysis, we compare women according to their HMO enrollment status at the first and second birth. DATA COLLECTION/EXTRACTION METHODS: Linked birth certificate/enrollment data were used to identify 4,917 women with two deliveries covered by Medicaid, one prior to the implementation of mandatory HMO enrollment (mid-1996) and one following implementation. Data for individual births were linked over time using a scrambled maternal Medicaid identification number. PRINCIPAL FINDINGS: The effects of HMO enrollment on prenatal care use and smoking were confined to Cuyahoga County, Ohio's largest county. In Cuyahoga, the implementation of mandatory enrollment was related to a significant deterioration in the timing of initiation of care, but an improvement in the number of prenatal visits. In that county also, women who smoked in their first pregnancy were less likely to smoke during the second pregnancy, compared to women in voluntary counties. Women residing in all the mandatory counties were less likely to have a repeat C-section. There were no effects on infant birth weight. The effects of women's own managed care status were inconsistent depending on the outcome examined; an interpretation of these results is hampered by selection issues. Changes over time in outcomes, both positive and negative, were more pronounced for African American women. CONCLUSIONS: With careful implementation and attention to women's individual differences as in Ohio, outcomes for pregnant women may improve with Medicaid managed care implementation. Quality monitoring should continue as Medicaid managed care becomes more widespread. More research is needed to identify the types of health maintenance organization activities that lead to improved outcomes.

An innovative blood lead screening program for Indian children.

There is little information on the lead levels of Indian children nationally. In the late 1990s, members of the Chippewa and Cree tribes living on the Rocky Boy Reservation near Box Elder, Montana, were concerned about environmental pollution and how it might be affecting the health of their children. With financial assistance from the Environmental Protection Agency, the tribes designed and implemented an innovative lead screening program for young children. Because most children on the reservation participated in WIC and Head Start, those programs were used to identify and screen close to 100% of young children on the reservation. The average blood lead level for children ages 1-5 on the Rocky Boy reservation was 2.4 micrograms/dL, which is not significantly different from that of children of the same age nationally. The project showed that Indian families will participate readily in screening programs that may improve their children's health.