Age- and Concentration-Dependent Elimination Half-Life of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Seveso Children

OBJECTIVE: Pharmacokinetic and statistical analyses are reported to elucidate key variables affecting 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elimination in children and adolescents. DESIGN: We used blood concentrations to calculate TCDD elimination half-life. Variables examined by statistical analysis include age, latency from exposure, sex, TCDD concentration and quantity in the body, severity of chloracne response, body mass index, and body fat mass. PARTICIPANTS: Blood was collected from 1976 to 1993 from residents of Seveso, Italy, who were < 18 years of age at the time of a nearby trichlorophenol reactor explosion in July 1976. RESULTS: TCDD half-life in persons < 18 years of age averaged 1.6 years while those ≥18 years of age averaged 3.2 years. Half-life is strongly associated with age, showing a cohort average increase of 0.12 year half-life per year of age or time since exposure. A significant concentration-dependency is also identified, showing shorter half-lives for TCDD concentrations > 400 ppt for children < 12 years of age and 700 ppt when including adults. Moderate correlations are also observed between half-life and body mass index, body fat mass, TCDD mass, and chloracne response. CONCLUSIONS: Children and adolescents have shorter TCDD half-lives and a slower rate of increase in half-life than adults, and this effect is augmented at higher body burdens. RELEVANCE: Modeling of TCDD blood concentrations or body burden in humans should take into account the markedly shorter elimination half-life observed in children and adolescents and concentration-dependent effects observed in persons > 400–700 ppt

Longevity and pleural mesothelioma: age-period-cohort analysis of incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program, 1973–2013

Abstract Objective This study investigates the hypothesis that an increasing fraction of incident pleural mesothelioma (PM) in the US population may be related to longevity, i.e., to expansion of the population over age 75 years with an age-related elevation in risk. An age-period-cohort analysis of the SEER 9 cancer registries (1973–2013) was conducted using 5-year intervals of age, calendar period, and birth cohort after stratification into four gender-age groups (male and female; 0–74 and 75+ years). Results Gender-specific time trends in age-adjusted PM incidence by age groups were observed. After adjusting for cohort effects, males in the 0–74-year age group experienced rapidly declining PM incidence rates following the observed peak in 1978–1982, whereas continuously increasing incidence rates were observed among older males. A significant cohort effect was also observed among males in both age groups, with peak incidence rates in the 1926–1930/1928–1932 birth cohorts and thereafter. The distinct period and cohort effects among males age 0–74 years may be driven by declining age-adjusted PM incidence rates corresponding to the decline in occupational asbestos exposures post-World War II, whereas the increasing time trend seen in both genders at age 75+ may reflect an increasing proportion due to longevity-related factors

Pathology, toxicology, and latency of irritant gases known to cause bronchiolitis obliterans disease: Does diacetyl fit the pattern?

AbstractBronchiolitis obliterans (BO) is a rare disease involving concentric bronchiolar fibrosis that develops rapidly following inhalation of certain irritant gases at sufficiently high acute doses. While there are many potential causes of bronchiolar lesions involved in a variety of chronic lung diseases, failure to clearly define the clinical features and pathological characteristics can lead to ambiguous diagnoses. Irritant gases known to cause BO follow a similar pathologic process and time course of disease onset in humans. Studies of inhaled irritant gases known to cause BO (e.g., chlorine, hydrochloric acid, ammonia, nitrogen oxides, sulfur oxides, sulfur or nitrogen mustards, and phosgene) indicate that the time course between causal chemical exposures and development of clinically significant BO disease is typically limited to a few months. The mechanism of toxic action exerted by these irritant gases generally involves widespread and severe injury of the epithelial lining of the bronchioles that leads to acute respiratory symptoms which can include lung edema within days. Repeated exposures to inhaled irritant gases at concentrations insufficient to cause marked respiratory distress or edema may lead to adaptive responses that can reduce or prevent severe bronchiolar fibrotic changes. Risk of BO from irritant gases is driven substantially by toxicokinetics affecting concentrations occurring at the bronchiolar epithelium. Highly soluble irritant gases that cause BO like ammonia generally follow a threshold-dependent cytotoxic mechanism of action that at sufficiently high doses results in severe inflammation of the upper respiratory tract and the bronchiolar epithelium concurrently. This is followed by acute respiratory distress, pulmonary edema, and post inflammatory concentric fibrosis that become clinically obvious within a few months. In contrast, irritant gases with lower solubility like phosgene also follow a threshold-dependent mechanism of cytotoxicity action but can exhibit more insidious and isolated bronchiolar tissue damage with a similar latency to fibrosis. To date, animal and human studies on the highly soluble gas, diacetyl, have not identified a coherent pattern of pathology and latency that would be expected based on studies of other known causes of bronchiolitis obliterans disease

Halo and spillover effect illustrations for selected beneficial medical devices and drugs

Abstract Background Negative news media reports regarding potential health hazards of implanted medical devices and pharmaceuticals can lead to a ‘negative halo effect,’ a phenomenon whereby judgments about a product or product type can be unconsciously altered even though the scientific support is tenuous. To determine how a ‘negative halo effect’ may impact the rates of use and/or explantation of medical products, we analyzed the occurrence of such an effect on three implanted medical devices and one drug: 1) intrauterine contraceptive devices (IUDs); 2) silicone gel-filled breast implants (SGBI); 3) metal-on-metal hip implants (MoM); and 4) the drug Tysabri. Methods Data on IUD use from 1965 to 2008 were gathered from the Department of Health and Human Services Vital and Health Statistics and peer-reviewed publications. Data regarding SGBI implant and explantation rates from 1989 to 2012 were obtained from the Institute of Medicine and the American Society of Plastic Surgeons. MoM implant and explantation data were extracted from the England and Wales National Joint Registry and peer-reviewed publications. Tysabri patient data were reported by Elan Corporation or Biogen Idec Inc. Data trends for all products were compared with historical recall or withdrawal events and discussed in the context of public perceptions following such events. Results We found that common factors altered public risk perceptions and patterns of continued use. First, a negative halo effect may be driven by continuing patient anxiety despite positive clinical outcomes. Second, negative reports about one product can spill over to affect the use of dissimilar products in the same category. Third, a negative halo effect on an entire category of medical devices can be sustained regardless of the scientific findings pertaining to safety. Fourth, recovery of a product’s safety reputation and prevalent use may take decades in the U.S., even while these products may exhibit widespread use and good safety records in other countries. Conclusions We conclude that the ‘negative halo effect’ associated with a stigma, rather than an objective risk-benefit assessment of medical products can increase negative health outcomes for patients due to reduced or inappropriate product usage

Headspace and small-chamber studies of airborne diacetyl release from selected food flavoring mixtures: activity coefficients and air modeling implications

<div><p>Laboratory studies were conducted to evaluate airborne release of diacetyl from selected mixtures simulating butter flavorings added to foods. The test materials included diacetyl (97% purity); 0.015%, 0.15%, 1.5%, and 3.0% diacetyl in a water/propylene glycol mixture; 1.5% diacetyl in deionized water or soybean oil; and 3% or 6% diacetyl in a commercial steam distillate from milk fermentation known as “butter starter distillate.” Diacetyl was quantified by gas chromatography with flame ionization detection. Expected concentration-dependent emission patterns based on liquid diacetyl content were demonstrated, but were significantly altered by mixture composition. Soybean oil and deionized water more readily released diacetyl when compared with starter distillate, propylene glycol solutions, and pure diacetyl. Measured diacetyl concentrations under static headspace and dynamic flow-chamber conditions were compared to estimated concentrations utilizing Raoult's law with published and fitted activity coefficient corrections for each mixture, indicating that published coefficients often understated the measured concentrations. It is concluded that headspace (static) and small-chamber (dynamic) measurements of airborne diacetyl provide data to assist in validating model-estimated airborne diacetyl concentrations by using mixture-specific activity coefficients. Implications of these empirical data for validating exposure estimates for diacetyl based on near-field/far-field modeling in workplace settings are discussed.</p></div

Liver tumor potency indicators for technical toxaphene and congeners simulating weathered toxaphene

<p>Technical toxaphene (TT) is a liver tumor promoter in B6C3F1 mice but not in F344 rats. To further evaluate dose-response relationships for weathered toxaphene, B6C3F1 mouse hepatocytes were treated with TT alone, five selected persistent congeners (p-26, p-50, p-62, Hx-Sed, and Hp-Sed), or two selected congener mixtures (simulating weathered toxaphene) and dose-response relationships were characterized for cytotoxicity and gap junction intercellular communication (GJIC) inhibition. Phenobarbital was included as a positive control for mouse liver tumor promotion and GJIC inhibition and dose ranges were calibrated to define benchmark dose concentrations. Each treatment group exhibited significant cytotoxicity and GJIC inhibition for at least one sex (M/F) after 3 and/or 24 h of treatment. Maximum GJIC inhibition was observed at certain noncytotoxic concentrations with sex-specific differences in relative potency estimated as the effective concentration at 20% inhibition (EC20); however, no significant EC20 differences were observed between the treatment groups. Analysis of mixture interactions at the EC20 showed that GJIC inhibition of the two weathered toxaphene mixtures was significantly less than additive compared to that for the component congeners. These findings suggest that the persistent toxaphene congener mixtures tested are not more tumorigenic than the parent insecticide mixture.</p

Proposed reference dose for toxaphene carcinogenicity based on constitutive androstane receptor-mediated mode of action

<p>Toxaphene is a liver tumor promoter in B6C3F1 mice but not in F344 rats or hamsters. Recent studies demonstrate that key events leading to the mouse liver tumor response for toxaphene are mediated by activation of the constitutive androstane receptor (CAR). Benchmark dose modeling was conducted on available data for five endpoints in B6C3F1 mouse liver tissue or cultured liver cells (tumor response, cytotoxicity, proliferation, gap junction intercellular communication inhibition, and CAR-mediated CYP2B10 induction) and for CAR activation in human HepG2 cells, all reported in previous studies. The available evidence supports a nonlinear CAR-mediated mode of action (MOA) for toxaphene-induced mouse tumors including demonstration of a J-shaped dose-response pattern for human CAR activation, indicating that linear risk extrapolation at low doses is not supported for this MOA. Based on analysis of benchmark dose lower confidence limits at 10% response (BMDL10) and no observed effect levels (NOELs) for potential key events in the mouse liver tumor MOA for toxaphene, an RfD of 0.13 mg/kg-d is proposed based on a the BMDL10 for human CAR activation in human HepG2 cells. This value is below candidate RfD values based on BMDL10 estimates for both mouse liver tumors and mouse hepatocyte proliferation and therefore can be considered protective for human risk of liver tumor promotion and other CAR-mediated adverse health effects based on available data.</p

Total cobalt determination in human blood and synovial fluid using inductively coupled plasma-mass spectrometry: method validation and evaluation of performance variables affecting metal hip implant patient samples

<div><p>Inductively coupled plasma with mass spectrometric detection (ICP-MS) has been used for clinical analysis of cobalt (Co) due to its sensitivity and specificity; however, media-specific validation studies are lacking. This study provides data on performance variables affecting differences between selected analytical platforms (Perkin Elmer and Agilent), tissue sample preparation, storage, and interferences affecting measurements in whole blood, serum, and synovial fluid. The limits of detection (LOD) range from 0.2–0.5 µg/L in serum and synovial fluid, and 0.6–1.7 µg Co/L in whole blood. The Agilent platform with collision reaction cell is more sensitive, while the Perkin Elmer platform with dynamic reaction cell demonstrates more polyatomic interferences near the LOD for serum and whole blood. Split sample analysis showed good accuracy, precision, and reproducibility between serum Co measurements using acid digestion or detergent dilution preparations for persons with metal hip implants or following supplement intake. The results demonstrated reliability of the ICP-MS methodology across the two analytical platforms and between two commercial laboratories for Co concentrations above 5 µg Co/L, but digestion procedures and polyatomic interferences may affect measurements in some media at lower concentrations. These studies validate the described ICP-MS methodology for clinical purposes with precautions at low cobalt concentrations (<5 µg Co/L).</p></div