Cost-utility analysis of prenatal diagnosis of congenital cardiac diseases using deep learning.

BACKGROUND: Deep learning (DL) is a new technology that can assist prenatal ultrasound (US) in the detection of congenital heart disease (CHD) at the prenatal stage. Hence, an economic-epidemiologic evaluation (aka Cost-Utility Analysis) is required to assist policymakers in deciding whether to adopt the new technology. METHODS: The incremental cost-utility ratios (CUR), of adding DL assisted ultrasound (DL-US) to the current provision of US plus pulse oximetry (POX), was calculated by building a spreadsheet model that integrated demographic, economic epidemiological, health service utilization, screening performance, survival and lifetime quality of life data based on the standard formula: CUR = Increase in Intervention Costs - Decrease in Treatment costs Averted QALY losses of adding DL to US & POX US screening data were based on real-world operational routine reports (as opposed to research studies). The DL screening cost of 145 USD was based on Israeli US costs plus 20.54 USD for reading and recording screens. RESULTS: The addition of DL assisted US, which is associated with increased sensitivity (95% vs 58.1%), resulted in far fewer undiagnosed infants (16 vs 102 [or 2.9% vs 15.4%] of the 560 and 659 births, respectively). Adoption of DL-US will add 1,204 QALYs. with increased screening costs 22.5 million USD largely offset by decreased treatment costs (20.4 million USD). Therefore, the new DL-US technology is considered "very cost-effective", costing only 1,720 USD per QALY. For most performance combinations (sensitivity > 80%, specificity > 90%), the adoption of DL-US is either cost effective or very cost effective. For specificities greater than 98% (with sensitivities above 94%), DL-US (& POX) is said to "dominate" US (& POX) by providing more QALYs at a lower cost. CONCLUSION: Our exploratory CUA calculations indicate the feasibility of DL-US as being at least cost-effective.

Application of probabilistic methods to address variability and uncertainty in estimating risks for non-cancer health effects.

Human health risk assessment currently uses the reference dose or reference concentration (RfD, RfC) approach to describe the level of exposure to chemical hazards without appreciable risk for non-cancer health effects in people. However, this "bright line" approach assumes that there is minimal risk below the RfD/RfC with some undefined level of increased risk at exposures above the RfD/RfC and has limited utility for decision-making. Rather than this dichotomous approach, non-cancer risk assessment can benefit from incorporating probabilistic methods to estimate the amount of risk across a wide range of exposures and define a risk-specific dose. We identify and review existing approaches for conducting probabilistic non-cancer risk assessments. Using perchloroethylene (PCE), a priority chemical for the U.S. Environmental Protection Agency under the Toxic Substances Control Act, we calculate risk-specific doses for the effects on cognitive deficits using probabilistic risk assessment approaches. Our probabilistic risk assessment shows that chronic exposure to 0.004 ppm PCE is associated with approximately 1-in-1,000 risk for a 5% reduced performance on the Wechsler Memory Scale Visual Reproduction subtest with 95% confidence. This exposure level associated with a 1-in-1000 risk for non-cancer neurocognitive deficits is lower than the current RfC for PCE of 0.0059 ppm, which is based on standard point of departure and uncertainty factor approaches for the same neurotoxic effects in occupationally exposed adults. We found that the population-level risk of cognitive deficit (indicating central nervous system dysfunction) is estimated to be greater than the cancer risk level of 1-in-100,000 at a similar chronic exposure level. The extension of toxicological endpoints to more clinically relevant endpoints, along with consideration of magnitude and severity of effect, will help in the selection of acceptable risk targets for non-cancer effects. We find that probabilistic approaches can 1) provide greater context to existing RfDs and RfCs by describing the probability of effect across a range of exposure levels including the RfD/RfC in a diverse population for a given magnitude of effect and confidence level, 2) relate effects of chemical exposures to clinical disease risk so that the resulting risk assessments can better inform decision-makers and benefit-cost analysis, and 3) better reflect the underlying biology and uncertainties of population risks.

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.

Consumer products as sources of chemical exposures to children: case study of triclosan.

PURPOSE OF REVIEW: Consumer products are often overlooked as sources of children's exposures to toxic chemicals. Various regulatory bodies have developed lists of chemicals of concern that can be found in products contacted by children. However, this information has not been summarized for health practitioners. This review organizes such chemicals and products into four categories, with the antibacterial agent triclosan used to illustrate the potential risks to children from a common ingredient in consumer products. RECENT FINDINGS: Biomonitoring, house dust, indoor air, and product testing document children's exposures to a wide variety of chemicals. An increasing number of epidemiology studies have shown associations between these exposures and health effects in children. Triclosan is an example of a chemical contained in high contact products (e.g., soaps, lotions, and toothpaste) not necessarily designed for children. Triclosan exposure in children has been associated with increased responsiveness to airway allergens, with it also capable of endocrine disruption. However, the utility and necessity of this chemical in consumer products has not been demonstrated in most cases. SUMMARY: Triclosan and the other examples provided show that a changing marketplace with little regulatory oversight of chemical uses can lead to unanticipated exposures and potential health risks to children.

Multinational Analysis of Estimated Health Care Costs Related to Extended-Interval Fixed Dosing of Checkpoint Inhibitors.

Importance: New dosing options for immune checkpoint inhibitors have recently been approved by the US Food and Drug Administration (FDA), including fixed dosing with extended intervals. Although the dose intensity appears the same, there is expected to be some waste with extended-interval dosing, as some drug remains in the bloodstream once a decision to stop treatment is made. The economic impact of extended-interval fixed dosing is unknown compared with standard-interval fixed dosing. Objective: To analyze the potential health care costs of using extended-interval fixed dosing instead of standard-interval fixed dosing. Design, Setting, and Participants: This economic evaluation used a pharmacoeconomic model to simulate 2 cohorts of patients with platinum-resistant metastatic urothelial cancer receiving pembrolizumab as second-line therapy at different dosing intervals using 2020 pricing data. Data were analyzed from 2020 to 2022. Exposures: The simulated patients received FDA-approved regimens of either 200 mg every 3 weeks or 400 mg every 6 weeks. Main Outcomes and Measures: The progression-free survival curve from the KEYNOTE-045 trial was used to estimate treatment duration. Drug, imaging, and administration costs were included in analyses. Sensitivity analyses were performed to assess how different imaging frequencies would affect the model results. The potential overall costs of using the 2 different dosing strategies were assessed. The base case was set in the US, while sensitivity analyses were set in several other countries. Results: In the base case analysis, dosing every 6 weeks instead of every 3 weeks resulted in an estimated 8.9% increase in pembrolizumab costs for the health care payer. Accounting for a decrease in infusion costs would result in an estimated net additional cost of $7483 per patient in the US (7.9% cost increase). In the US, this would amount to an increase of approximately $28 million annually for health care payers. Similar percentages in cost estimate increases were found for health care payers around the world, such as in Israel, where the net additional cost would be $5491 per patient. Conclusions and Relevance: This economic evaluation assessed and quantified the potential increased costs related to extended-interval fixed dosing of pembrolizumab. The model method could be applied to other diseases and other drugs for which there has been a movement toward extended-interval dosing. Results may differ in other diseases owing to differing disease courses and patient profiles.

Cadmium risk assessment in relation to background risk of chronic kidney disease.

Cadmium's noncancer effects on the kidney represent a useful case study of the unified approach to toxicity assessment described in a recent National Academy of Science report. Cadmium (Cd) is recognized to exert toxic effects on the kidney at low dose without a demonstrable threshold. The implications of current dietary exposure and regulatory limits can be understood in terms of risk for chronic kidney disease (CKD) since both Cd adverse effects and CKD are defined by the same continous parameter (loss in glomerular filtration rate [GFR]). The Cd dose response on GFR derived from a study of Swedish women was applied to the baseline population distribution of GFR to determine the effect of Cd on CKD risk. The baseline population of 47.8-yr-old women was estimated to carry a 10% rate of Stage 3 CKD, similar to national statistics in the United States. A chronic daily dose of Cd at 1 µg/kg/d produced a left shift in this distribution and increased the population risk of CKD by an estimated 25%. A 10-fold lower Cd dose was associated with an increase in population risk of 2.7%, and this rose to 3.4% in 75-yr-olds. These estimates (1) provide additional perspective to the traditional risk/no risk approaches used in setting U.S. Environmental Protection Agency (EPA) reference doses (RfD) and Agency for Toxic Substances and Disease Registry (ATSDR) minimum risk levels (MRL) and (2) demonstrate the utility of considering chemical additivity to background disease in assessing human risk.

Mechanistic Considerations in 1,4-Dioxane Cancer Risk Assessment.

The risk assessment of many carcinogens involves extrapolation across large exposure differences between the dose levels used in animal studies and the much lower human exposures. This is true for 1,4-dioxane which has a consistent liver carcinogenic effect in both genders of rats and mice. These data have been applied to risk assessment assuming a linear low dose extrapolation in some cases but non-linear or threshold models have been used in others. This choice hinges on our understanding of the 1,4-dioxane cancer mechanism. While 1,4-dioxane is not genotoxic in standard test batteries and has non-linear toxicokinetics, the mechanism for its carcinogenic effect remains unknown and is an active area of research. This review summarizes the possible modes of action for this chemical, data gaps and application to risk assessment. We find that the cytotoxicity/hyperplasia and metabolic saturation hypotheses do not explain the carcinogenic response and do not take into account 1,4-dioxane's induction of its own metabolism, leading to less likelihood for saturation during chronic exposure. There is evidence for other mechanisms, especially oxidative stress associated with the induction of CYP2E1 and in vivo genotoxicity that is not seen in vitro. The dose response for these effects needs further exploration compared to the time course and dose response for 1,4-dioxane-induced carcinogenesis. An additional consideration is the manner in which these 1,4-dioxane effects may augment naturally occurring and disease-related processes that contribute to the increasing rate of human liver cancer. These factors add to the rationale for using a non-threshold linear approach for extrapolating to low dose for this carcinogen, which is consistent with the default for carcinogens which do not have a clearly defined mode of action.

Oxidative stress and genotoxicity in 1,4-dioxane liver toxicity as evidenced in a mouse model of glutathione deficiency.

1,4-Dioxane (DX) is a synthetic chemical used as a stabilizer for industrial solvents. Recent occurrence data show widespread and significant contamination of drinking water with DX in the US. DX is classified by the International Agency for Research on Cancer as a group 2B carcinogen with the primary target organ being the liver in animal studies. Despite the exposure and cancer risk, US EPA has not established a drinking water Maximum Contaminant Level (MCL) for DX and a wide range of drinking water targets have been established across the US and by Health Canada. The DX carcinogenic mechanism remains unknown; this information gap contributes to the varied approaches to its regulation. Our recent mice study indicated alterations in oxidative stress response accompanying DNA damage as an early change by high dose DX (5000 ppm) in drinking water. Herein, we report a follow-up study, in which we used glutathione (GSH)-deficient glutamate-cysteine ligase modifier subunit (Gclm)-null mice to investigate the role of redox homeostasis in DX-induced liver cytotoxicity and genotoxicity. Gclm-null and wild-type mice were exposed to DX for one week (1000 mg/kg/day by oral gavage) or three months (5000 ppm in drinking water). Subchronic exposure of high dose DX caused mild liver cytotoxicity. DX induced assorted molecular changes in the liver including: (i) a compensatory nuclear factor erythroid 2-related factor 2 (NRF2) anti-oxidative response at the early stage (one week), (ii) progressive CYP2E1 induction, (iii) development of oxidative stress, as evidenced by persistent NRF2 induction, oxidation of GSH pool, and accumulation of the lipid peroxidation by-product 4-hydroxynonenal, and (iv) elevations in oxidative DNA damage and DNA repair response. These DX-elicited changes were exaggerated in GSH-deficient mice. Collectively, the current study provides additional evidence linking redox dysregulation to DX liver genotoxicity, implying oxidative stress as a candidate mechanism of DX liver carcinogenicity.

Human papillomavirus vaccine introduction in low-income and middle-income countries: guidance on the use of cost-effectiveness models.

BACKGROUND: The World Health Organization (WHO) recommends that the cost effectiveness of introducing human papillomavirus (HPV) vaccination is considered before such a strategy is implemented. However, developing countries often lack the technical capacity to perform and interpret results of economic appraisals of vaccines. To provide information about the feasibility of using such models in a developing country setting, we evaluated models of HPV vaccination in terms of their capacity, requirements, limitations and comparability. METHODS: A literature review identified six HPV vaccination models suitable for low-income and middle-income country use and representative of the literature in terms of provenance and model structure. Each model was adapted by its developers using standardised data sets representative of two hypothetical developing countries (a low-income country with no screening and a middle-income country with limited screening). Model predictions before and after vaccination of adolescent girls were compared in terms of HPV prevalence and cervical cancer incidence, as was the incremental cost-effectiveness ratio of vaccination under different scenarios. RESULTS: None of the models perfectly reproduced the standardised data set provided to the model developers. However, they agreed that large decreases in type 16/18 HPV prevalence and cervical cancer incidence are likely to occur following vaccination. Apart from the Thai model (in which vaccine and non-vaccine HPV types were combined), vaccine-type HPV prevalence dropped by 75% to 100%, and vaccine-type cervical cancer incidence dropped by 80% to 100% across the models (averaging over age groups). The most influential factors affecting cost effectiveness were the discount rate, duration of vaccine protection, vaccine price and HPV prevalence. Demographic change, access to treatment and data resolution were found to be key issues to consider for models in developing countries. CONCLUSIONS: The results indicated the usefulness of considering results from several models and sets of modelling assumptions in decision making. Modelling groups were prepared to share their models and expertise to work with stakeholders in developing countries. Please see related article: http://www.biomedcentral.com/1741-7007/9/55.

Development and evaluation of a harmonized physiologically based pharmacokinetic (PBPK) model for perchloroethylene toxicokinetics in mice, rats, and humans.

This article reports on the development of a "harmonized" PBPK model for the toxicokinetics of perchloroethylene (tetrachloroethylene or perc) in mice, rats, and humans that includes both oxidation and glutathione (GSH) conjugation of perc, the internal kinetics of the oxidative metabolite trichloroacetic acid (TCA), and the urinary excretion kinetics of the GSH conjugation metabolites N-Acetylated trichlorovinyl cysteine and dichloroacetic acid. The model utilizes a wider range of in vitro and in vivo data than any previous analysis alone, with in vitro data used for initial, or "baseline," parameter estimates, and in vivo datasets separated into those used for "calibration" and those used for "evaluation." Parameter calibration utilizes a limited Bayesian analysis involving flat priors and making inferences only using posterior modes obtained via Markov chain Monte Carlo (MCMC). As expected, the major route of elimination of absorbed perc is predicted to be exhalation as parent compound, with metabolism accounting for less than 20% of intake except in the case of mice exposed orally, in which metabolism is predicted to be slightly over 50% at lower exposures. In all three species, the concentration of perc in blood, the extent of perc oxidation, and the amount of TCA production is well-estimated, with residual uncertainties of ~2-fold. However, the resulting range of estimates for the amount of GSH conjugation is quite wide in humans (~3000-fold) and mice (~60-fold). While even high-end estimates of GSH conjugation in mice are lower than estimates of oxidation, in humans the estimated rates range from much lower to much higher than rates for perc oxidation. It is unclear to what extent this range reflects uncertainty, variability, or a combination. Importantly, by separating total perc metabolism into separate oxidative and conjugative pathways, an approach also recommended in a recent National Research Council review, this analysis reconciles the disparity between those previously published PBPK models that concluded low perc metabolism in humans and those that predicted high perc metabolism in humans. In essence, both conclusions are consistent with the data if augmented with some additional qualifications: in humans, oxidative metabolism is low, while GSH conjugation metabolism may be high or low, with uncertainty and/or interindividual variability spanning three orders of magnitude. More direct data on the internal kinetics of perc GSH conjugation, such as trichlorovinyl glutathione or tricholorvinyl cysteine in blood and/or tissues, would be needed to better characterize the uncertainty and variability in GSH conjugation in humans.

Polymorphism in the DNA repair enzyme XRCC1: utility of current database and implications for human health risk assessment.

Genetic polymorphisms are increasingly recognized as sources of variability not only in toxicokinetic but also in toxicodynamic response to environmental agents. XRCC1 is involved in base excision repair (BER) of DNA; it has variant genotypes that are associated with modified repair function. This analysis focuses on four polymorphisms: three in the coding region that affect protein structure and one in an upstream regulatory sequence that affects gene expression. The Arg399Gln variant is the most widely studied with evidence supporting a quantitative effect of genotype on phenotype. The homozygous variant (Gln/Gln) can have 3-4-fold diminished capacity to remove DNA adducts and oxidized DNA damage. This variant is relatively common in Caucasians and Asians where approximately 10% are homozygous variant. In contrast, the Arg194Trp variant appears to protect against genotoxic effects although the degree to which DNA repair is enhanced by this polymorphism is uncertain. The homozygous variant is rare in Caucasians and African Americans but it is present at 7% in Asians. A third coding region polymorphism at codon 280 appears to decrease repair function but additional quantitative information is needed and the homozygous variant is rare across populations studied. A polymorphism in an upstream promoter binding sequence (-77T>C) appears to lower XRCC1 levels by decreasing gene expression. Based upon genotype effect on phenotype and allele frequency, the current analysis finds that the codon 399 and upstream (-77) polymorphisms have the greatest potential to affect the toxicodynamic response to DNA damaging agents. However, the implications for risk assessment are limited by the likelihood that polymorphisms in multiple BER genes interact to modulate DNA repair.

Benzothiazole toxicity assessment in support of synthetic turf field human health risk assessment.

Synthetic turf fields cushioned with crumb rubber may be a source of chemical exposure to those playing on the fields. Benzothiazole (BZT) may volatilize from crumb rubber and result in inhalation exposure. Benzothiazole has been the primary rubber-related chemical found in synthetic turf studies. However, risks associated with BZT have not been thoroughly assessed, primarily because of gaps in the database. This assessment provides toxicity information for a human health risk assessment involving BZT detected at five fields in Connecticut. BZT exerts acute toxicity and is a respiratory irritant and dermal sensitizer. In a genetic toxicity assay BZT was positive in Salmonella in the presence of metabolic activation. BZT metabolism involves ring-opening and formation of aromatic hydroxylamines, metabolites with mutagenic and carcinogenic potential. A structural analogue 2-mercaptobenzothiazole (2-MBZT) was more widely tested and so is used as a surrogate for some endpoints. 2-MBZT is a rodent carcinogen with rubber industry data supporting an association with human bladder cancer. The following BZT toxicity values were derived: (1) acute air target of 110 µg/m(3) based upon a BZT RD(50) study in mice relative to results for formaldehyde; (2) a chronic noncancer target of 18 µg/m(3) based upon the no-observed-adverse-effect level (NOAEL) in a subchronic dietary study in rats, dose route extrapolation, and uncertainty factors that combine to 1000; (3) a cancer unit risk of 1.8E-07/µg-m(3) based upon a published oral slope factor for 2-MBZT and dose-route extrapolation. While there are numerous uncertainties in the BZT toxicology database, this assessment enables BZT to be quantitatively assessed in risk assessments involving synthetic turf fields. However, this is only a screening-level assessment, and research that better defines BZT potency is needed.

Human health risk assessment of synthetic turf fields based upon investigation of five fields in Connecticut.

Questions have been raised regarding possible exposures when playing sports on synthetic turf fields cushioned with crumb rubber. Rubber is a complex mixture with some components possessing toxic and carcinogenic properties. Exposure is possible via inhalation, given that chemicals emitted from rubber might end up in the breathing zone of players and these players have high ventilation rates. Previous studies provide useful data but are limited with respect to the variety of fields and scenarios evaluated. The State of Connecticut investigated emissions associated with four outdoor and one indoor synthetic turf field under summer conditions. On-field and background locations were sampled using a variety of stationary and personal samplers. More than 20 chemicals of potential concern (COPC) were found to be above background and possibly field-related on both indoor and outdoor fields. These COPC were entered into separate risk assessments (1) for outdoor and indoor fields and (2) for children and adults. Exposure concentrations were prorated for time spent away from the fields and inhalation rates were adjusted for play activity and for children's greater ventilation than adults. Cancer and noncancer risk levels were at or below de minimis levels of concern. The scenario with the highest exposure was children playing on the indoor field. The acute hazard index (HI) for this scenario approached unity, suggesting a potential concern, although there was great uncertainty with this estimate. The main contributor was benzothiazole, a rubber-related semivolatile organic chemical (SVOC) that was 14-fold higher indoors than outdoors. Based upon these findings, outdoor and indoor synthetic turf fields are not associated with elevated adverse health risks. However, it would be prudent for building operators to provide adequate ventilation to prevent a buildup of rubber-related volatile organic chemicals (VOC) and SVOC at indoor fields. The current results are generally consistent with the findings from studies conducted by New York City, New York State, the U.S. Environmental Protection Agency (EPA), and Norway, which tested different kinds of fields and under a variety of weather conditions.

Synthetic turf field investigation in Connecticut.

The primary purpose of this study was to characterize the concentrations of volatile organic compounds (VOC), semivolatile organic compounds (SVOC), rubber-related chemicals such as benzothiazole (BZT) and nitrosamine, and particulate matter (PM(10)) in air at synthetic turf crumb rubber fields. Both new and older fields were evaluated under conditions of active use. Three types of fields were targeted: four outdoor crumb rubber fields, one indoor facility with crumb rubber turf, and an outdoor natural grass field. Background samples were collected at each field on grass. Personal air sampling was conducted for VOC, BZT, nitrosamines, and other chemicals. Stationary air samples were collected at different heights to assess the vertical profile of release. Air monitoring for PM(10) was conducted at one height. Bulk samples of turf grass and crumb rubber were analyzed, and meteorological data were recorded. Results showed that personal concentrations were higher than stationary concentrations and were higher on turf than in background samples for certain VOC. In some cases, personal VOC concentrations from natural grass fields were as high as those on turf. Naphthalene, BZT, and butylated hydroxytoluene (BHT) were detected in greater concentration at the indoor field compared to the outdoor fields. Nitrosamine air levels were below reporting levels. PM(10) air concentrations were not different between on-field and upwind locations. All bulk lead (Pb) samples were below the public health target of 400 ppm. More research is needed to better understand air quality at indoor facilities. These field investigation data were incorporated into a separate human health risk assessment.

Genetic polymorphism in metabolism and host defense enzymes: implications for human health risk assessment.

Genetic polymorphisms in xenobiotic metabolizing enzymes can have profound influence on enzyme function, with implications for chemical clearance and internal dose. The effects of polymorphisms have been evaluated for certain therapeutic drugs but there has been relatively little investigation with environmental toxicants. Polymorphisms can also affect the function of host defense mechanisms and thus modify the pharmacodynamic response. This review and analysis explores the feasibility of using polymorphism data in human health risk assessment for four enzymes, two involved in conjugation (uridine diphosphoglucuronosyltransferases [UGTs], sulfotransferases [SULTs]), and two involved in detoxification (microsomal epoxide hydrolase [EPHX1], NADPH quinone oxidoreductase I [NQO1]). This set of evaluations complements our previous analyses with oxidative and conjugating enzymes. Of the numerous UGT and SULT enzymes, the greatest likelihood for polymorphism effect on conjugation function are for SULT1A1 (*2 polymorphism), UGT1A1 (*6, *7, *28 polymorphisms), UGT1A7 (*3 polymorphism), UGT2B15 (*2 polymorphism), and UGT2B17 (null polymorphism). The null polymorphism in NQO1 has the potential to impair host defense. These highlighted polymorphisms are of sufficient frequency to be prioritized for consideration in chemical risk assessments. In contrast, SNPs in EPHX1 are not sufficiently influential or defined for inclusion in risk models. The current analysis is an important first step in bringing the highlighted polymorphisms into a physiologically based pharmacokinetic (PBPK) modeling framework.

Prevention, screening and treatment of colorectal cancer: a global and regional generalized cost effectiveness analysis.

BACKGROUND: Regional generalized cost-effectiveness estimates of prevention, screening and treatment interventions for colorectal cancer are presented. METHODS: Standardised WHO-CHOICE methodology was used. A colorectal cancer model was employed to provide estimates of screening and treatment effectiveness. Intervention effectiveness was determined via a population state-transition model (PopMod) that simulates the evolution of a sub-regional population accounting for births, deaths and disease epidemiology. Economic costs of procedures and treatment were estimated, including programme overhead and training costs. RESULTS: In regions characterised by high income, low mortality and high existing treatment coverage, the addition of screening to the current high treatment levels is very cost-effective, although no particular intervention stands out in cost-effectiveness terms relative to the others.In regions characterised by low income, low mortality with existing treatment coverage around 50%, expanding treatment with or without screening is cost-effective or very cost-effective. Abandoning treatment in favour of screening (no treatment scenario) would not be cost effective.In regions characterised by low income, high mortality and low treatment levels, the most cost-effective intervention is expanding treatment. CONCLUSIONS: From a cost-effectiveness standpoint, screening programmes should be expanded in developed regions and treatment programmes should be established for colorectal cancer in regions with low treatment coverage.

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.

Issues in estimating smoking attributable mortality in Israel.

BACKGROUND: The US Centres for Disease Control provides a widely used online user-friendly computational program, called SAMMEC (Smoking Attributable Mortality, Morbidity and Economic Costs) to produce estimates of tobacco-related mortality. However, the SAMMEC tool loses accuracy because it lacks flexibility in deciding which diseases enter into the calculations, has estimates of relative risk (RR) attributable to smoking based on old studies, and does not allow for the latency period that occurs between initial exposure and mortality. METHODS: Smoking attributable mortality (SAM) due to active smoking in Israel was estimated with the approach used by SAMMEC taking into account past and present smoking prevalence (lag-times) as well as using new and expanded disease categories. RESULTS: Around 50.3% of the increase from the un-lagged SAM estimate of 3859 deaths to the final SAM estimate of 8664 deaths in 2003 is attributable to the introduction of lag times. More robust estimates of risk accounted for a further 29.6% of the increase. While 21.2% is attributable to the inclusion of additional disease categories, only 1.5% was attributable to the widening of existing diseases categories. CONCLUSION: This difference in estimates is attributable to expansion of the list of diseases included, updating the estimates of RR for smoking-attributable death, and the use of smoking prevalence from previous years to more accurately reflect the effect of tobacco use on disease occurrence. There is a need to establish an 'authority' to implement a multi-faceted intervention strategy to decrease the considerable burden from smoking in Israel.

Kratom Adulterated with Phenylethylamine and Associated Intracerebral Hemorrhage: Linking Toxicologists and Public Health Officials to Identify Dangerous Adulterants.

INTRODUCTION: Kratom is derived from the plant Mitragyna speciosa which is indigenous to Southeast Asia. Active compounds, mitragynine and 7-hydroxymitragynine, cause mild stimulant and opioid agonist effects. Although reported to have potential benefits in the treatment of opioid use disorder, efficacy remains uncertain while adverse health effects have been reported. A compounding concern is the presence of adulterants given that this is an unregulated product. CASE DETAILS: A 54-year-old fitness instructor who used an online purchased kratom product regularly for one year developed stimulatory effects and suffered a large hemorrhagic stroke with a close temporal relationship to ingestion of a different kratom product from the one he regularly used. A collaborative investigation by medical toxicologists, a regional poison center, the state public health laboratory, and public health officials determined that his new kratom product was adulterated with phenylethylamine (PEA). DISCUSSION: We report a case of PEA adulterated kratom purchased and used with resultant adverse effects. PEA is structurally similar to amphetamine and is known to produce sympathomimetic effects. It is possible the stimulatory effect of PEA resulted in a marked and transient increase in blood pressure resulting in hemorrhagic stroke. CONCLUSION: Medical toxicologists should form working relationships with laboratories and public health officials to aid in early identification of adulterated products that carry risk to the general population.

Quantitative approach for incorporating methylmercury risks and omega-3 fatty acid benefits in developing species-specific fish consumption advice.

BACKGROUND: Despite general agreement about the toxicity of methylmercury (MeHg), fish consumption advice remains controversial. Concerns have been raised that negative messages will steer people away from fish and omega-3 fatty acid (FA) benefits. One approach is to provide advice for individual species that highlights beneficial fish while cautioning against riskier fish. OBJECTIVES: Our goal in this study was to develop a method to quantitatively analyze the net risk/benefit of individual fish species based on their MeHg and omega-3 FA content. METHODS: We identified dose-response relationships for MeHg and omega-3 FA effects on coronary heart disease (CHD) and neurodevelopment. We used the MeHg and omega-3 FA content of 16 commonly consumed species to calculate the net risk/benefit for each species. RESULTS: Estimated omega-3 FA benefits outweigh MeHg risks for some species (e.g., farmed salmon, herring, trout); however, the opposite was true for others (swordfish, shark). Other species were associated with a small net benefit (e.g., flounder, canned light tuna) or a small net risk (e.g., canned white tuna, halibut). These results were used to place fish into one of four meal frequency categories, with the advice tentative because of limitations in the underlying dose-response information. Separate advice appears warranted for the neurodevelopmental risk group versus the cardiovascular risk group because we found a greater net benefit from fish consumption for the cardiovascular risk group. CONCLUSIONS: This research illustrates a framework for risk/benefit analysis that can be used to develop categories of consumption advice ranging from "do not eat" to "unlimited," with the caveat that unlimited may need to be tempered for certain fish (e.g., farm-raised salmon) because of other contaminants and end points (e.g., cancer risk). Uncertainties exist in the underlying dose-response relationships, pointing in particular to the need for more research on the adverse effects of MeHg on cardiovascular end points.