Dose-response Thresholds Research Articles

Rapid predictive dosimetry for radioembolization.

Economics of today's busy clinical practice demand both time and cost-efficient methods of predictive dosimetry for liver radioembolisation. A rapid predictive schema adapted from the Medical Internal Radiation Dose (MIRD) method i.e., Partition Model, has been devised that can be completed within minutes. This rapid schema may guide institutions that do not have access to software capable of comprehensive auto-segmentation of lung, tumour and non-tumorous liver, or where rigorous artery-specific tomographic predictive dosimetry is unfeasible for the routine clinical workflow. This rapid schema is applicable to any beta-emitting radiomicrosphere, although absorbed dose-response thresholds will differ according to device. Sampling errors in lung, tumour and non-tumorous liver will compound and propagate throughout this schema. This rapid schema achieves efficiency in lieu of accuracy. The user must be mindful of potentially large sampling errors and assumes all responsibility. Any suspicion of significant error requires the user to revert back to standard-of-care methods.

Effect of nanosecond pulsed electric fields (nsPEFs) on coronavirus survival

Previous work demonstrated inactivation of influenza virus by GHz frequency electromagnetic fields. Despite theoretical and experimental results, the underlying mechanism driving this inactivation remains unknown. One hypothesis is that the electromagnetic field is causing damage to the virion membrane (and therefore changing spike protein orientation) rendering the virus unable to attach and infect host cells. Towards examining this hypothesis, our group employed nanosecond pulsed electric fields (nsPEFs) as a surrogate to radiofrequency (RF) exposure to enable exploration of dose response thresholds of electric field-induced viral membrane damage. In summary, Bovine coronavirus (BCoV) was exposed, in suspension, to mono and bipolar 600-ns pulsed electric fields (nsPEFs) at two amplitudes (12.5 and 25 kV/cm) and pulse numbers [0 (sham), 1, 5, 10, 100, and 1000] at a 1 Hz (Hz) repetition rate. The temperature rise immediately after exposure(s) was measured using thermocouples to differentiate effects of the electric field (E-field) and heating (i.e., the thermal gradient). Inactivation of BCoV was evaluated by infecting HRT-18G host cells and assessing differences in virus infectivity days after exposure. Our results show that 600 nsPEFs, both bipolar and monopolar, can reduce the infectivity of coronaviruses at various amplitudes, pulse numbers, and pulse polarity. Interestingly, we observed that bipolar exposures appeared to be more efficient at lower exposure intensities than monopolar pulses. Future work should focus on experiments to identify the mechanism underlying nsPEF-induced viral inactivation.

Voxel-based dosimetry predicting treatment response and related toxicity in HCC patients treated with resin-based Y90 radioembolization: a prospective, single-arm study

BackgroundThere is an increasing body of evidence indicating Y90 dose thresholds for tumor response and treatment-related toxicity. These thresholds are poorly studied in resin Y90, particularly in hepatocellular carcinoma (HCC).PurposeTo evaluate the efficacy of prospective voxel-based dosimetry for predicting treatment response and adverse events (AEs) in patients with HCC undergoing resin-based Y90 radioembolization.Materials and methodsThis correlative study was based on a prospective single-arm clinical trial (NCT04172714), which evaluated the efficacy of low/scout (555 MBq) activity of resin-based Y90 for treatment planning. Partition model was used with goal of tumor dose (TD) > 200 Gy and non-tumoral liver dose (NTLD) < 70 Gy for non-segmental therapies. Single compartment dose of 200 Gy was used for segmentectomies. Prescribed Y90 activity minus scout activity was administered for therapeutic Y90 followed by Y90-PET/CT. Sureplan® (MIM Software, Cleveland, OH) was used for dosimetry analysis. Treatment response was evaluated at 3 and 6 months. Receiver operating characteristic curve determined TD response threshold for objective response (OR) and complete response (CR) as well as non-tumor liver dose (NTLD) threshold that predicted AEs.ResultsN = 30 patients were treated with 33 tumors (19 segmental and 14 non-segmental). One patient died before the first imaging, and clinical follow-up was excluded from this analysis. Overall, 26 (81%) of the tumors had an OR and 23 (72%) had a CR. A mean TD of 253 Gy predicted an OR with 92% sensitivity and 83% specificity (area under the curve (AUC = 0.929, p < 0.001). A mean TD of 337 Gy predicted a CR with 83% sensitivity and 89% specificity (AUC = 0.845, p < 0.001). A mean NTLD of 81 and 87 Gy predicted grade 3 AEs with 100% sensitivity and 100% specificity in the non-segmental cohort at 3- and 6-month post Y90, respectively.ConclusionIn patients with HCC undergoing resin-based Y90, there are dose response and dose toxicity thresholds directly affecting outcomes.Clinical trial number: NCT04172714.

Determination of Tumor Dose Response Thresholds in Patients with Chemorefractory Intrahepatic Cholangiocarcinoma Treated with Resin and Glass-based Y90 Radioembolization.

To compare the efficacies of glass and resin-based Yttrium-90 microspheres by comparing absorbed tumor dose (TD) with both tumor response (TR) and overall survival (OS) in patients with chemorefractory intrahepatic cholangiocarcinoma (ICC). Post-Y90 treatment bremsstrahlung SPECT/CT of 38 consecutive patients receiving 45 treatments (21 resin microspheres, 24 glass microspheres) were analyzed retrospectively. MIM software v6.9.4 (MIM Software Inc, Cleveland, OH) was used to calculate targeted tumors' dose volume histogram. Modified Response Evaluation Criteria in Solid Tumors was used to evaluate tumor response 3months post-treatment. Kaplan Meier estimation was used for survival analysis. T-test was used to compare the devices on various dosimetric parameters. Thresholds for TD to predict TR with ≥ 80% specificity were as follows: mean TD (Resin: 78.9Gy; Glass: 254.7Gy), maximum TD (Resin: 162.9Gy; Glass: 591Gy), minimum TD (Resin: 53.7Gy; Glass: 149.1Gy). Microsphere type had no effect on survival from first Y90 (Resin: 11.2 mo; Glass 10.9 mo [p = 0.548]). In patients receiving resin microspheres, mean TD ≥ 75Gy or maximum TD ≥ 150Gy was associated with median OS of 20.2 mo compared to 6.5 mo for those receiving less (p = 0.001, 0.002, respectively). For patients treated with glass microspheres, those receiving a mean TD ≥ 150Gy had a median OS of 14.6 mo vs. 2.6 mo for those receiving less (p = 0.031). TD thresholds predictive of TR and OS differ significantly between glass and resin microspheres. However, microsphere type has no impact on survival in patients with chemorefractory ICC. Level 3, Retrospective Study.

Potency and power

Building on a rich body of feminist scholarship on estrogen, this account interrogates how potent estrogenic cosmetics and consumer product labels emerged together, through the regulatory practices of scientists and lawyers, in mid-century Canada. Composed from archival and other primary sources, the story traces the development of Canada’s first cosmetic regulations – which applied only to cosmetic products containing estrogens. In 1944, “sex hormones” had been the first substances for which the Department of National Health and Welfare adopted labels in lieu of dose or potency standards under the Food and Drugs Act. With dose-response thresholds thus written out of the Sex Hormone Regulations, in 1949, regulators devised a new type of consumer product label that warned women to use estrogenic cosmetic products “with care”. Further regulatory amendments in 1950 appeared, on their face, to require positive proof of safety for estrogenic cosmetics, However, through varied administrative and enforcement practices that hinged upon “directions for use” in product labels, National Health officials quietly reintroduced dose-response logics back into estrogen regulation. As legal technologies for disciplining women consumers to regulate their own exposures, product labels were becoming instrumental. With labeling, estrogen catalyzed an early example of risk regulation in Canada.

Standardised quantitative radioiodine SPECT/CT Imaging for multicentre dosimetry trials in molecular radiotherapy

The SEL-I-METRY trial (EudraCT No 2015-002269-47) is the first multicentre trial to investigate the role of 123I and 131I SPECT/CT-based tumour dosimetry to predict response to radioiodine therapy. Standardised dosimetry methodology is essential to provide a robust evidence-base for absorbed dose–response thresholds for molecular radiotherapy (MRT). In this paper a practical standardised protocol is used to establish the first network of centres with consistent methods of radioiodine activity quantification.Nine SPECT/CT systems at eight centres were set-up for quantitative radioiodine imaging. The dead-time of the systems was characterised for up to 2.8 GBq 131I. Volume dependent calibration factors were measured on centrally reconstructed images of 123I and 131I in six (0.8–196 ml) cylinders. Validation of image quantification using these calibration factors was performed on three systems, by imaging a 3D-printed phantom mimicking a patient’s activity distribution. The percentage differences between the activities measured in the SPECT/CT image and those measured by the radionuclide calibrator were calculated. Additionally uncertainties on the SPECT/CT-based activities were calculated to indicate the limit on the quantitative accuracy of this method.For systems set-up to image high 131I count rates, the count rate versus activity did not peak below 2.8 GBq and fit a non-paralysable model. The dead-times and volume-dependent calibration factors were comparable between systems of the same model and crystal thickness. Therefore a global calibration curve could be fitted to each. The errors on the validation phantom activities’ were comparable to the measurement uncertainties derived from uncertainty analysis, at 10% and 16% on average for 123I and 131I respectively in a 5 cm sphere.In conclusion, the dead-time and calibration factors varied between centres, with different models of system. However, global calibration factors may be applied to the same system model with the same crystal thickness, to simplify set-up of future multi-centre MRT studies.

Relation of Total Sugars, Sucrose, Fructose, and Added Sugars With the Risk of Cardiovascular Disease: A Systematic Review and Dose-Response Meta-analysis of Prospective Cohort Studies

ObjectiveTo determine the association of total and added fructose-containing sugars on cardiovascular disease (CVD) incidence and mortality. MethodsMEDLINE, EMBASE and Cochrane Library were searched from January 1, 1980, to July 31, 2018. Prospective cohort studies assessing the association of reported intakes of total, sucrose, fructose and added sugars with CVD incidence and mortality in individuals free from disease at baseline were included. Risk estimates were pooled using the inverse variance method, and dose-response analysis was modeled. ResultsEligibility criteria were met by 24 prospective cohort comparisons (624,128 unique individuals; 11,856 CVD incidence cases and 12,224 CVD mortality cases). Total sugars, sucrose, and fructose were not associated with CVD incidence. Total sugars (risk ratio, 1.09 [95% confidence interval, 1.02 to 1.17]) and fructose (1.08 [1.01 to 1.15]) showed a harmful association for CVD mortality, there was no association for added sugars and a beneficial association for sucrose (0.94 [0.89 to 0.99]). Dose-response analyses showed a beneficial linear dose-response gradient for sucrose and nonlinear dose-response thresholds for harm for total sugars (133 grams, 26% energy), fructose (58 grams, 11% energy) and added sugars (65 grams, 13% energy) in relation to CVD mortality (P<.05). The certainty of the evidence using GRADE was very low for CVD incidence and low for CVD mortality for all sugar types. ConclusionCurrent evidence supports a threshold of harm for intakes of total sugars, added sugars, and fructose at higher exposures and lack of harm for sucrose independent of food form for CVD mortality. Further research of different food sources of sugars is needed to define better the relationship between sugars and CVD. Registrationclinicaltrials.gov, NCT01608620

Risk Analysis Implications of Dose-Response Thresholds for NLRP3 Inflammasome-Mediated Diseases: Respirable Crystalline Silica and Lung Cancer as an Example.

Chronic inflammation mediates an extraordinarily wide range of diseases. Recent progress in understanding intracellular inflammasome assembly, priming, activation, cytokine signaling, and interactions with mitochondrial reactive oxygen species, lysosome disruption, cell death, and prion-like polymerization and spread of inflammasomes among cells, has potentially profound implications for dose–response modeling. This article discusses mechanisms of exposure concentration and duration thresholds for NOD-like receptor protein 3 (NLRP3)-mediated inflammatory responses and develops a simple biomathematical model of the onset of exposure-related tissue-level chronic inflammation and resulting disease risks, focusing on respirable crystalline silica (RCS) and lung cancer risk as an example. An inflammation-mediated 2-stage clonal expansion model of RCS-induced lung cancer is proposed that explains why relatively low estimated concentrations of RCS (eg, <1 mg/m3) do not increase lung cancer risk and why even high occupational concentrations increase risk only modestly (typically relative risk <2). The model of chronic inflammation implies a dose–response threshold for excess cancer risk, in contrast to traditional linear-no-threshold assumptions. If this implication is correct, then concentrations of crystalline silica (or amphibole asbestos fibers, or other environmental challenges that act via the NLRP3 inflammasome) below the threshold do not cause chronic inflammation and resulting elevated risks of inflammation-mediated diseases.

Biological mechanisms of non-linear dose-response for respirable mineral fibers

Sufficiently high and prolonged inhalation exposures to some respirable elongated mineral particles (REMPs), notably including amphibole asbestos fibers, can increase risk of inflammation-mediated diseases including malignant mesothelioma, pleural diseases, fibrosis, and lung cancer. Chronic inflammation involves ongoing activation of the NLRP3 inflammasome, which enables immune cells to produce potent proinflammatory cytokines IL-1β and IL-18. Reactive oxygen species (ROS) (in particular, mitochondrial ROS) contribute to NRLP3 activation via a well-elucidated mechanism involving oxidation of reduced thioredoxin and association of thioredoxin-interacting protein with NLRP3. Lysosomal destabilization, efflux of cytosolic potassium ions and influx of calcium ions, signals from damaged mitochondria, both translational and post-translational controls, and prion-like polymerization have increasingly clear roles in regulating NLRP3 activation.As the molecular biology of inflammation-mediated responses to REMP exposure becomes clearer, a practical question looms: What do these mechanisms imply for the shape of the dose-response function relating exposure concentrations and durations for EMPs to risk of pathological responses? Dose-response thresholds or threshold-like nonlinearities can arise from (a) Cooperativity in assembly of supramolecular signaling complexes; (b) Positive feedback loops and bistability in regulatory networks; (c) Overwhelming of defensive barriers maintaining homeostasis; and (d) Damage thresholds, as in lysosome destabilization-induced activation of NLRP3. Each of these mechanisms holds for NLRP3 activation in response to stimuli such as REMP exposures. It is therefore timely to consider the implications of these advances in biological understanding for human health risk assessment with dose-response thresholds.

Sex- and dose-dependent abuse liability of repeated subanesthetic ketamine in rats

RationaleSubanesthetic ketamine (KET) elicits rapid, robust, but transient antidepressant effects. KET's antidepressant actions can be augmented and maintained for a longer duration when repeatedly delivered. However, KET is recreationally abused, raising long-term treatment safety concerns. Women are more likely than men to seek treatment for depression, escalate from casual to compulsive drug use, and are more sensitive to antidepressants. Similarly, female rodents are more sensitive than males to KET's rapid antidepressant-like behavioral effects; dose-response thresholds in these assays equal 2.5 and 5.0mg/kg (i.p.), respectively. This suggests the utility of preclinical rodent models in optimizing sex-differential KET therapy protocols and minimizing adverse drug reactions. ObjectivesHere, we assessed behavioral and biochemical correlates of abuse liability following six serial KET treatments on alternating days at three subanesthetic, antidepressant-like doses (2.5, 5.0, or 10mg/kg, i.p.) in adult male and female rats. A potential role for ΔFosB-mediated transcription in the nucleus accumbens is outlined in the context of KET-mediated locomotor sensitization. ResultsAntidepressant-like threshold doses (2.5, 5.0mg/kg KET) failed to evoke a conditioned place preference in all animals, but only males positively responded to a higher dose (10mg/kg). Behavioral sensitization to 5.0 or 10mg/kg KET's locomotor-activating effects was established in both sexes, and females' sensitized response to 5.0mg/kg was greater than males'. KET-induced hyperlocomotion positively correlated with ΔFosB protein expression in the nucleus accumbens. rAAV-ΔJunD inhibition of ΔFosB-mediated transcription in the accumbens failed to block locomotor sensitization to 10mg/kg KET. ConclusionsThese data suggest that in rats, six alternating-day treatments with 2.5mg/kg KET do not induce apparent behavioral signatures of abuse liability despite accumulation of ΔFosB protein in the accumbens. Additionally, females are more sensitive than males to KET's locomotor-stimulant properties, both acutely and after repeated treatments. More studies are needed to determine brain regions and neural mechanisms responsible for KET-induced behavioral adaptations and to extrapolate these data to inform sex-dependent strategies for long-term KET therapy protocols for depression.

Beyond mean pharyngeal constrictor dose for beam path toxicity in non-target swallowing muscles: Dose–volume correlates of chronic radiation-associated dysphagia (RAD) after oropharyngeal intensity modulated radiotherapy

Purpose/objective(s)We sought to identify swallowing muscle dose–response thresholds associated with chronic radiation-associated dysphagia (RAD) after IMRT for oropharyngeal cancer. Materials/methodsT1–4 N0–3 M0 oropharyngeal cancer patients who received definitive IMRT and systemic therapy were examined. Chronic RAD was coded as any of the following ⩾12months post-IMRT: videofluoroscopy/endoscopy detected aspiration or stricture, gastrostomy tube and/or aspiration pneumonia. DICOM-RT plan data were autosegmented using a custom region-of-interest (ROI) library and included inferior, middle and superior constrictors (IPC, MPC, and SPC), medial and lateral pterygoids (MPM, LPM), anterior and posterior digastrics (ADM, PDM), intrinsic tongue muscles (ITM), mylo/geniohyoid complex (MHM), genioglossus (GGM), masseter (MM), buccinator (BM), palatoglossus (PGM), and cricopharyngeus (CPM), with ROI dose–volume histograms (DVHs) calculated. Recursive partitioning analysis (RPA) was used to identify dose–volume effects associated with chronic-RAD, for use in a multivariate (MV) model. ResultsOf 300 patients, 34 (11%) had chronic-RAD. RPA showed DVH-derived MHM V69 (i.e. the volume receiving⩾69Gy), GGM V35, ADM V60, MPC V49, and SPC V70 were associated with chronic-RAD. A model including age in addition to MHM V69 as continuous variables was optimal among tested MV models (AUC 0.835). ConclusionIn addition to SPCs, dose to MHM should be monitored and constrained, especially in older patients (>62-years), when feasible.

Phthalates and critically ill neonates: device-related exposures and non-endocrine toxic risks.

To assess the types and magnitudes of non-endocrine toxic risks to neonates associated with medical device-related exposures to di(2-ethylhexyl)phthalate (DEHP). Dose-response thresholds for DEHP toxicities were determined from published data, as were the magnitudes of DEHP exposures resulting from neonatal contact with polyvinyl chloride (PVC) devices. Standard methods of risk assessment were used to determine safe levels of DEHP exposure in neonates, and hazard quotients were calculated for devices individually and in aggregate. Daily intake of DEHP for critically ill preterm infants can reach 16 mg/kg per day, which is on the order of 4000 and 160,000 times higher than desired to avoid reproductive and hepatic toxicities, respectively. The non-endocrine toxicities of DEHP are similar to complications experienced by preterm neonates. DEHP exposures in neonatal intensive care are much higher than estimated safe limits, and might contribute to common early and chronic complications of prematurity. Concerns about phthalates should be expanded beyond endocrine disruption.

Dose-Response Thresholds for Progressive Diseases

Many diseases, including cancers, heart diseases, and lung diseases, can usefully be viewed as arising from disruption of feedback control systems that normally maintain homeostasis of tissues and cell populations. Excessive exposure can destabilize feedback control loops, leading to sustained elevation of variables to saturated levels and clinical consequences such as chronic unresolved inflammation, destruction of tissue (as in emphysema), proliferation of cell populations (as in lung cancer), and increases in reactive oxygen species and protease levels (as in coronary heart diseases and chronic obstructive lung disease). We propose a framework for understanding how exposure can destabilize normally homeostatic feedback control systems and create sustained imbalances and elevated levels of disease-related variables, by creating a new, locally stable, alternative equilibrium for the dynamic system, in addition to its normal (homeostatic) equilibrium. The resulting model, which we call alternative-equilibria (AE) theory, implies the existence of an exposure threshold below which transition to the alternative equilibrium (potential disease) state will not occur. Once this threshold is exceeded, progression to the alternative equilibrium continues spontaneously, even without further exposure. These predictions may help to explain patterns observed in experimental and epidemiological data for diseases such as COPD, silicosis, and inflammation-mediated lung cancer.

Response of red‐cockaded woodpeckers to military training operations

Response of red‐cockaded woodpeckers to military training operations

Mercury demethylation in waterbird livers: Dose–response thresholds and differences among species

We assessed methylmercury (MeHg) demethylation in the livers of adults and chicks of four waterbird species that commonly breed in San Francisco Bay: American avocets, black-necked stilts, Caspian terns, and Forster's terns. In adults (all species combined), we found strong evidence for a threshold model where MeHg demethylation occurred above a hepatic total mercury concentration threshold of 8.51 +/- 0.93 microg/g dry weight, and there was a strong decline in %MeHg values as total mercury (THg) concentrations increased above 8.51 microg/g dry weight. Conversely, there was no evidence for a demethylation threshold in chicks, and we found that %MeHg values declined linearly with increasing THg concentrations. For adults, we also found taxonomic differences in the demethylation responses, with avocets and stilts showing a higher demethylation rate than that of terns when concentrations exceeded the threshold, whereas terns had a lower demethylation threshold (7.48 +/- 1.48 microg/g dry wt) than that of avocets and stilts (9.91 +/- 1.29 microg/g dry wt). Finally, we assessed the role of selenium (Se) in the demethylation process. Selenium concentrations were positively correlated with inorganic Hg in livers of birds above the demethylation threshold but not below. This suggests that Se may act as a binding site for demethylated Hg and may reduce the potential for secondary toxicity. Our findings indicate that waterbirds demethylate mercury in their livers if exposure exceeds a threshold value and suggest that taxonomic differences in demethylation ability may be an important factor in evaluating species-specific risk to MeHg exposure. Further, we provide strong evidence for a threshold of approximately 8.5 microg/g dry weight of THg in the liver where demethylation is initiated.

Analysis of the mitotic exit control system using locked levels of stable mitotic cyclin

Cyclin-dependent kinase (Cdk) both promotes mitotic entry (spindle assembly and anaphase) and inhibits mitotic exit (spindle disassembly and cytokinesis), leading to an elegant quantitative hypothesis that a single cyclin oscillation can function as a ratchet to order these events. This ratchet is at the core of a published ODE model for the yeast cell cycle. However, the ratchet model requires appropriate cyclin dose–response thresholds. Here, we test the inhibition of mitotic exit in budding yeast using graded levels of stable mitotic cyclin (Clb2). In opposition to the ratchet model, stable levels of Clb2 introduced dose-dependent delays, rather than hard thresholds, that varied by mitotic exit event. The ensuing cell cycle was highly abnormal, suggesting a novel reason for cyclin degradation. Cdc14 phosphatase antagonizes Clb2–Cdk, and Cdc14 is released from inhibitory nucleolar sequestration independently of stable Clb2. Thus, Cdc14/Clb2 balance may be the appropriate variable for mitotic regulation. Although our results are inconsistent with the aforementioned ODE model, revision of the model to allow Cdc14/Clb2 balance to control mitotic exit corrects these discrepancies, providing theoretical support for our conclusions.

Social recovery model: an 8-year investigation of adolescent 12-step group involvement following inpatient treatment.

Despite widespread use of 12-step treatment approaches and referrals to Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) by youth providers, little is known about the significance of these organizations in youth addiction recovery. Furthermore, existing evidence is based mostly on short-term follow-up and is limited methodologically. Adolescent inpatients (n = 160; mean age = 16, 40% female) were followed at 6-months, and at 1, 2, 4, 6, and 8 years posttreatment. Time-lagged, generalized estimating equations modeled treatment outcome in relation to AA/NA attendance controlling for static and time-varying covariates. Robust regression (locally weighted scatterplot smoothing) explored dose-response thresholds of AA/NA attendance on outcome. The AA/NA attendance was common and intensive early posttreatment, but declined sharply and steadily over the 8-year period. Patients with greater addiction severity and those who believed that they could not use substances in moderation were more likely to attend. Despite declining attendance, the effects related to AA/NA remained significant and consistent. Greater early participation was associated with better long-term outcomes. Even though many youth discontinue AA/NA over time, attendees appear to benefit, and more severely substance-involved youth attend most. Successful early posttreatment engagement of youth in abstinence-supportive social contexts, such as AA/NA, may have long-term implications for alcohol and drug involvement into young adulthood.

Television Time and Continuous Metabolic Risk in Physically Active Adults

Among Australian adults who met the public health guideline for the minimum health-enhancing levels of physical activity, we examined the dose-response associations of television-viewing time with continuous metabolic risk variables. Data were analyzed on 2031 men and 2033 women aged > or = 25 yr from the 1999-2000 Australian Diabetes, Obesity and Lifestyle study without clinically diagnosed diabetes or heart disease, who reported at least 2.5 h.wk of moderate- to vigorous-intensity physical activity. Waist circumference, resting blood pressure, and fasting and 2-h plasma glucose, triglycerides, and high-density-lipoprotein cholesterol (HDL-C) were measured. The cross-sectional associations of these metabolic variables with quartiles and hours per day of self-reported television-viewing time were examined separately for men and for women. Analyses were adjusted for age, education, income, smoking, diet quality, alcohol intake, parental history of diabetes, and total physical activity time, as well as menopausal status and current use of postmenopausal hormones for women. Significant, detrimental dose-response associations of television-viewing time were observed with waist circumference, systolic blood pressure, and 2-h plasma glucose in men and women, and with fasting plasma glucose, triglycerides, and HDL-C in women. The associations were stronger in women than in men, with significant gender interactions observed for triglycerides and HDL-C. Though waist circumference attenuated the associations, they remained statistically significant for 2-h plasma glucose in men and women, and for triglycerides and HDL-C in women. In a population of healthy Australian adults who met the public health guideline for physical activity, television-viewing time was positively associated with a number of metabolic risk variables. These findings support the case for a concurrent sedentary behavior and health guideline for adults, which is in addition to the public health guideline on physical activity.

Risk assessment methodologies for exposure of great horned owls (Bubo virginianus) to PCBs on the Kalamazoo river, Michigan

Dietary exposures of great horned owls (GHO; Bubo virginianus) to polychlorinated biphenyls (PCBs) in the terrestrial food web at the Kalamazoo River, Michigan, USA, were examined. Average potential daily doses (APDD) in GHO diets were 7- to 10-fold and 3-fold greater at the more contaminated location versus a reference location for site-specific exposures quantified as total PCBs and 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQ(WHO-Avian)), respectively. Wetland/aquatic prey contributed significantly to PCB exposure and APDD. Estimates of risk based on comparison of modeled dietary intake (e.g., APDD) to toxicity reference values (TRVs), using a hazard quotient (HQ) methodology, varied between diet composition methods (mass basis vs numeric basis). Mass-basis compositions yielded greater HQs at all sites. Potential risks associated with dietary exposures ("bottom-up" risk assessment methodology) were less than (HQ < 1) benchmarks for effects. This result is consistent with risk estimates based on concentrations in tissues ("top-down" risk assessment methodology), and indicated PCBs posed no significant risk to terrestrial raptor species. Colocated and concurrent studies that evaluated GHO reproductive performance (nestling productivity) and relative abundance were consistent with results of the risk assessment. Measures of risk based on HQs were consistent with direct measures of ecologically relevant endpoints (reproductive fitness). Uncertainty in risk estimates is contributed during the selection of TRVs for effects in GHO based on TEQ(WHO-Avian) because of the absence of species-specific, dose-response thresholds. This evaluation indicated that a multiple-lines-of-evidence approach provided the best estimate of risk.

Do dose response thresholds exist for genotoxic alkylating agents?

The demonstration and acceptance of dose response thresholds for genotoxins may have substantial implications for the setting of safe exposure levels. Here we test the hypothesis that direct-acting DNA reactive agents may exhibit thresholded dose responses. We examine the potential mechanisms involved in such thresholded responses, particularly in relation to those of alkylating agents. As alkylating agents are representative model DNA reactive compounds with well characterized activities and DNA targets, they could help shed light on the general mechanisms involved in thresholded dose responses for genotoxins. Presently, thresholds have mainly been described for agents with non-DNA targets. We pay particular attention here to the contribution of DNA repair to genotoxic thresholds. A review of the literature shows that limited threshold data for alkylating agents are currently available, but the contribution of DNA repair in thresholded dose responses is suggested by several studies. The existence of genotoxic thresholds for alkylating agents methylmethanesulfonate is also supported here by data from our laboratory. Overall, it is clear that different endpoints induced by the same alkylator, can possess different dose response characteristics. This may have an impact on the setting of safe exposure levels for such agents. The limited information available concerning the dose response relationships of alkylators can nevertheless lead to the design of experiments to investigate the mechanisms that may be involved in threshold responses. Through using paired alkylators inducing different lesions, repaired by different pathways, insights into the processes involved in genotoxic thresholds may be elucidated. Furthermore, as alkyl-guanine-DNA transferase, base excision repair and mismatch repair appear to contribute to genotoxic thresholds for alkylators, cells deficient in these repair processes may possess altered dose responses compared with wild-type cells and this approach may help understand the contribution of these repair pathways to the production of thresholds for genotoxic effects in general. Finally, genotoxic thresholds are currently being described for acute exposures to single agents in vitro, however, dose response data for chronic exposures to complex mixtures are, as yet, a long way off.