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Studies have associated the human respiratory syncytial virus which causes seasonal childhood acute bronchitis and bronchiolitis (CABs) with climate change and air pollution. We investigated this association using the insurance claims data of 3,965,560 children aged ≤ 12 years from Taiwan from 2006-2016. The monthly average incident CABs increased with increasing PM

Background Evidences have shown that the stroke risk associated with long-term exposure to particulate matter with an aerodynamic diameter of ≤2.5 μm (PM2.5) varies among people in North America, Europe and Asia, but studies in Asia rarely evaluated the association by stroke type. We examined whether long-term exposure to PM2.5 is associated with developing all strokes, ischemic stroke and hemorrhagic stroke. Methods The retrospective cohort study consisted of 1,362,284 adults identified from beneficiaries of a universal health insurance program in 2011. We obtained data on air pollutants and meteorological measurements from air quality monitoring stations across Taiwan in 2010–2015. Annual mean levels of all environmental measurements in residing areas were calculated and assigned to cohort members. We used Cox proportional hazards models to estimate hazard ratio (HR) and 95% confidence interval (CI) of developing stroke associated with 1-year mean levels of PM2.5 at baseline in 2010, and yearly mean levels from 2010 to 2015 as the time-varying exposure, adjusting for age, sex, income and urbanization level. Results During a median follow-up time of 6.0 years, 12,942 persons developed strokes, 9919 (76.6%) were ischemic. The adjusted HRs (95% CIs) per interquartile range increase in baseline 1-year mean PM2.5 were 1.03 (1.00–1.06) for all stroke, 1.06 (1.02–1.09) for ischemic stroke, and 0.95 (0.89–1.10) for hemorrhagic stroke. The concentration-response curves estimated in the models with and without additional adjustments for other environmental measurements showed a positively linear association between baseline 1-year mean PM2.5 and ischemic stroke at concentrations greater than 30 μg/m3, under which no evidence of association was observed. There was an indication of an inverse association between PM2.5 and hemorrhagic stroke, but the association no longer existed after controlling for nitrogen dioxide or ozone. We found similar shape of the concentration-response association in the Cox regression models with time-varying PM2.5 exposures. Conclusion Long-term exposure to PM2.5 might be associated with increased risk of developing ischemic stroke. The association with high PM2.5 concentrations remained significant after adjustment for other environmental factors.

Thiodiglycolic acid (TDGA) is a major metabolite of vinyl chloride monomer (VCM), and it has been suggested as an exposure biomarker for VCM. The validity of this biomarker when the level of VCM is less than 5 ppm, however, is questionable. The objective of this article is to evaluate the feasibility of using urinary TDGA as a biomarker of VCM exposure in a community health risk assessment setting where the concentration of VCM in air is typically very low (likely below 1 ppm). To achieve this objective, we examine the fraction of urinary TDGA associated with different levels of VCM exposures of three studies from different countries, using estimations of the TDGA metabolite predicted by a PBPK model. It is demonstrated that differences in background TDGA have considerable effect on the adequacy of TDGA as a biomarker of VCM. We conclude that, in a community health assessment setting, TDGA should not be used as an exposure biomarker for VCM without having a proper control group, and a PBPK model can be used first to determine whether or not the amount of TDGA in urine is of concern.

No study has ever investigated how ambient temperature and PM2.5 mediate rotavirus infection (RvI) in children. We used insurance claims data from Taiwan in 2006–2012 to evaluate the RvI characteristics in children aged ≤ 9. The RvI incidence rates were higher in colder months, reaching the highest in March (117.0/100 days), and then declining to the lowest in July (29.2/100 days). The age–sex-specific average incident cases were all higher in boys than in girls. Stratified analysis by temperature (2.5 (3) showed that the highest incidence was 16.4/100 days at average temperatures of 2.5 of 31.5–41.9 μg/m3, with Poisson regression analysis estimating an adjusted relative risk (aRR) of 1.26 (95% confidence interval (CI) = 1.11–1.43), compared to the incidence at the reference condition (2.5 < 17.5 μg/m3). As the temperature increased, the incident RvI cases reduced to 4.84 cases/100 days (aRR = 0.40, 95% CI = 0.35–0.45) when it was >25 °C with PM2.5 < 17.5 μg/m3, or to 9.84/100 days (aRR = 0.81, 95% CI = 0.77–0.93) when it was >25 °C with PM2.5 > 42 μg/m3. The seasonal RvI is associated with frequent indoor personal contact among children in the cold months. The association with PM2.5 could be an alternative assessment due to temperature inversion.

This article discusses cessation lag and effect lingering and their potential applications to dose-response analysis in risk assessment. Effect lingering can be used to analyze epidemiological data by uncovering the hidden biological implication related to disease endpoints, thereby advancing current characterization efforts and reducing risk assessment uncertainties. To illustrate the approach, as well as to better characterize the role of age of initiation and duration of smoking in carcinogenesis, we apply the concept of lingering effect to smoking and lung cancer data from the Cancer Prevention Study II.

The existing extensive laboratory data on trichloroethylene (TCE) and its two metabolites, dichloroacetic (DCA) and trichloroacetic (TCA), are used to explore the relationship among these three compounds. Under the hypothesis that these compounds induce liver tumors in mice through promotion of preexisting initiated cells, it is demonstrated that DCA alone could be responsible for all the response of carcinomas in liver of B6CF(1) mice. The focus of this paper is on how a plausible biological assumption could impact on low-dose risk estimates, rather than on the risk estimate per se. The findings suggest that low-dose risk estimates to humans would be overestimated unless the different background rates between mice and humans are properly accounted for.

Environmental regulations aimed at reducing cancer risks usually have the effect of reducing exposure to a carcinogen at the time the regulation is implemented. The reduction of cancer risk may occur shortly after the reduced exposure or after a considerable period of time. The time of risk reduction associated with exposure reduction will vary by compound. Some recommended measures of the economic benefits associated with environmental regulations are sensitive to the timing of the risk reductions and cannot be effectively addressed by the conventional dose-response procedures. This paper introduces the concept and methodologies for calculating cessation lag effects, with the specific goal of answering the following questions: (1) How many cancer cases are avoided at age t after cessation (or reduction) of exposure concentration? and (2) How long does the effect of an exposure last after exposure has terminated (or been reduced)? The proposed procedures do not require more information than what is required by the conventional dose-response procedures for which cumulative or an averaged lifetime exposure is used.

The objective of this paper is twofold: (1) to provide insight on the simplified MVK model of carcinogenesis (a model proposed by Moolgavkar and colleagues) by revealing the relationship between the Armitage-Doll two-stage model and the simplified MVK model; and (2) to extend the Armitage-Doll two-stage model to one with time-varying (piece-wise constant) parameters. It is shown that the simplified MVK model is a special case of the Armitage-Doll two-stage model, and many applications of the simplified MVK model involving intermittent exposures or exposures to different compounds in different time periods can be derived easily from the Armitage-Doll two-stage model with piece-wise constant parameters. The limitations of the Armitage-Doll two-stage model are discussed.

Vinyl chloride (VC) is used as an example to demonstrate how biological information can be incorporated into quantitative risk assessment. The information included is the pharmacokinetics of VC in animals and humans and the data-generated hypothesis that VC primarily affects the initiation stage of the multistage carcinogenesis. The emphasis in this paper is on the improvement of risk assessment methodology rather than the risk assessment of VC per se. Sufficient data are available to construct physiologically-based pharmacokinetic models for both animals and humans. These models are used to calculate the metabolized dose corresponding to exposure scenarios in animals and in humans. On the basis of the data on liver angiosarcomas and carcinomas in rats, the cancer risk per unit of metabolized dose is comparable, irrespective of routes (oral or inhalation) of exposure. The tumor response from an intermittent/partial lifetime exposure is shown to be consistent with that from a lifetime exposure when VC is assumed to affect the first (initiation) stage of the multistage carcinogenic process. Furthermore, the risk estimates calculated on the basis of animal data are shown to be consistent with the human experience.

PURPOSE: To evaluate the safety and efficacy of topical recombinant human nerve growth factor (rhNGF) for treating moderate-to-severe neurotrophic keratitis (NK), a rare degenerative corneal disease resulting from loss of corneal innervation. DESIGN: Phase II multicenter, randomized, double-masked, vehicle-controlled trial. PARTICIPANTS: Patients with stage II (moderate) or stage III (severe) NK in one eye. METHODS: The REPARO Phase II study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10μg/ml, 20 μg/ml, or vehicle. Treatment was administered 6 drops per day for 8 weeks. Patients then entered a 48- or 56-week follow-up period. Safety was assessed in all patients who received study drug, while efficacy was by intention to treat. MAIN OUTCOME MEASURES: Corneal healing (defined as

Neurotrophic keratitis/keratopathy (NK), a rare degenerative corneal disease, lacks effective pharmacologic therapies.1 Because NK pathology involves trigeminal nerve damage and loss of corneal innervation, nerve growth factor (NGF) is surmised to promote healing of NK.2 Preliminary studies with murine NGF demonstrated efficacy for treating corneal neurotrophic ulcers;3 however, the complex tertiary structure of NGF has complicated the production of recombinant human NGF (rhNGF) suitable for clinical development. To this end, we developed an Escherichia coli–derived rhNGF formulation that demonstrated to be well tolerated and safe for topical ophthalmic use in a phase I study in healthy volunteers.4 We report phase I results of topical rhNGF for patients with moderate-to-severe NK.