Fenofibrate-associated changes in renal function and relationship to clinical outcomes among individuals with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) experience.

AIMS/HYPOTHESIS: Fenofibrate has been noted to cause an elevation in serum creatinine in some individuals. Participants in the Action to Control Cardiovascular Risk in Diabetes Lipid Study were studied to better characterise who is at risk of an increase in creatinine level and to determine whether those with creatinine elevation have a differential risk of adverse renal or cardiovascular outcomes. METHODS: A fenofibrate-associated creatinine increase (FACI) was defined as an increase in serum creatinine of at least 20% from baseline to month 4 in participants assigned to fenofibrate. Baseline patient characteristics, and baseline and 4-month drug, clinical, laboratory characteristics and study outcomes were examined by FACI status. RESULTS: Of the sample, 48% of those randomised to receive fenofibrate had at least a 20% increase in serum creatinine within 4 months. In multivariable analysis, participants who were older, male, used an ACE inhibitor at baseline, used a thiazolidinedione (TZD) at 4 months post-randomisation, had baseline CVD, and had lower baseline serum creatinine and LDL-cholesterol levels were all more likely to meet the criteria for FACI. Participants in the FACI group were also more likely to have a decrease in their serum triacylglycerol level from baseline to 4 months. No differences in study outcomes were seen by FACI criteria. CONCLUSIONS/INTERPRETATION: Several characteristics predict a rapid rise in serum creatinine upon starting fenofibrate. Participants who met the criteria for FACI also had a greater change in triacylglycerol levels. In the setting of careful renal function surveillance and reduction of fenofibrate dose as indicated, no increase in renal disease or cardiovascular outcome was seen in those individuals demonstrating FACI. TRIAL REGISTRATION: ClincalTrials.gov: NCT00000620. FUNDING: The ACCORD Trial was supported by grants (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035 and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; by General Clinical Research Centers and by the Clinical and Translational Science Awards. Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, sanofi-aventis US and Takeda Pharmaceuticals provided study medications, equipment or supplies.

One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial.

AIM: The aim of this study was to compare the efficacy and safety of once-daily human glucagon-like peptide-1 analogue liraglutide with dipeptidyl peptidase-4 inhibitor sitagliptin, each added to metformin, over 52 weeks in individuals with type 2 diabetes. METHODS: In an open-label, parallel-group trial, metformin-treated participants were randomised to liraglutide 1.2 mg/day (n=225), liraglutide 1.8 mg/day (n=221) or sitagliptin 100 mg/day (n=219) for 26 weeks (main phase). Participants continued the same treatment in a 26-week extension. RESULTS: Liraglutide (1.2 or 1.8 mg) was superior to sitagliptin for reducing HbA(1c) from baseline (8.4-8.5%) to 52 weeks: -1.29% and -1.51% vs. -0.88% respectively. Estimated mean treatment differences between liraglutide and sitagliptin were as follows: -0.40% (95% confidence interval -0.59 to -0.22) for 1.2 mg and -0.63% (-0.81 to -0.44) for 1.8 mg (both p<0.0001). Weight loss was greater with liraglutide 1.2 mg (-2.78 kg) and 1.8 mg (-3.68 kg) than sitagliptin (-1.16 kg) (both p<0.0001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly more with liraglutide 1.8 mg than with sitagliptin (p=0.03). Proportions of participants reporting adverse events were generally comparable; minor hypoglycaemia was 8.1%, 8.3% and 6.4% for liraglutide 1.2 mg, 1.8 mg and sitagliptin respectively. Gastrointestinal side effects, mainly nausea, initially occurred more frequently with liraglutide, but declined after several weeks. CONCLUSION: Liraglutide provides greater sustained glycaemic control and body weight reduction over 52 weeks. Treatment satisfaction was significantly greater with 1.8 mg liraglutide, similar to 26-week results. The safety profiles of liraglutide and sitagliptin are consistent with previous reports.

Liraglutide improves treatment satisfaction in people with Type 2 diabetes compared with sitagliptin, each as an add on to metformin.

AIMS: Patient-reported outcomes from clinical trials offer insight into the impact of disease on health-related quality of life, including treatment satisfaction. This patient-reported outcomes evaluation was a substudy of a 26-week randomized, open-label trial comparing the once-daily injectable human GLP-1 analogue liraglutide with once-daily oral sitagliptin, both added to metformin. The patient reported outcomes substudy aimed to evaluate treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) at baseline and 26 weeks. METHODS: In the main 26-week randomized, open-label study (n =658), liraglutide, 1.2 or 1.8 mg, injected with a pen, led to greater HbA1c reduction than oral sitagliptin, 100 mg once daily, both added to metformin = 1500 mg daily: mean HbA1c reduction was 1.5, 1.2 and 0.9% (7, 10 and 14 mmol/mol) for liraglutide 1.8 mg, 1.2 mg and sitagliptin, respectively (P < 0.0001 for both liraglutide doses vs. sitagliptin) and liraglutide patients lost more weight (3 vs.1 kg; P < 0.0001). In this patient-reported outcomes substudy (liraglutide 1.8 mg, n = 171; 1.2 mg, n = 164; sitagliptin, n = 170) DTSQ scores were analyzed by ANCOVA with treatment and country as fixed effects and baseline value as covariate. RESULTS: Overall treatment satisfaction, calculated by adding satisfaction scores for `current treatment', `convenience', `flexibility', `understanding', `recommend', and `continue', improved in all groups at 26 weeks; greater improvement with liraglutide (4.35 and 3.51 vs. 2.96; P = 0.03 for liraglutide 1.8 mg vs. sitagliptin) may reflect greater HbA1c reduction and weight loss. Patients perceived themselves to be hyperglycaemic significantly less frequently with liraglutide 1.8 mg (difference = -0.88; P < 0.0001) and 1.2 mg ( -0.49; P = 0.01). Perceived frequency of hypoglycaemia was similar across all groups. CONCLUSIONS: Injectable liraglutide may lead to greater treatment satisfaction than oral sitagliptin, potentially by facilitating greater improvement in glycaemic control, weight loss and/ or perception of greater treatment efficacy.

In support of an early polypharmacy approach to the treatment of type 2 diabetes.

Type 2 diabetes (T2DM) is a multifaceted disease, characterized by hyperglycaemia, resulting from a combination of insulin resistance, impaired incretin action and ß-cell dysfunction leading to relative insulin deficiency. Although traditional anti-diabetes agents improve hyperglycaemia, they do so at a cost, which may entail hypoglycemia and increased body weight; exacerbating dyslipidemia, hypertension and components of insulin resistance and metabolic syndrome associated with T2DM-potentially increasing cardiovascular risk. At diagnosis, many patients with T2DM are treated with medical nutritional therapy (MNT) and exercise, then single or multiple oral anti-diabetes agents until treatment failure, when insulin is used. This strategy has been challenged by recommendations for polypharmacy approaches to the treatment of T2DM, as current strategies are unable to improve multiple aspects of the disease, nor are they likely to address underlying pathophysiology. Although the 2009 American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) treatment algorithm recommends a stepwise approach with MNT and metformin, later adding oral agents, incretin-based therapies or insulin, some experts have recommended a more aggressive approach. In his 2008 ADA Banting Lecture, Dr. Ralph DeFronzo recommended early treatment with metformin, TZD and exenatide at initiation of therapy. The authors' of this article recommend an aggressive early polypharmacy approach addressing underlying pathophysiology, including the incretin defect-with MNT and exercise, metformin and an incretin-based therapy and/or basal insulin if glycemic goal is not achieved within 3 months. This approach attempts to modify the disease, aiming for tight glycemic control, weight loss, reduced hypoglycemia, improvements to hypertension, dyslipidemia and insulin resistance-and improved cardiovascular outcomes.

A comparison between simplified and intensive dose-titration algorithms using AIR inhaled insulin for insulin-naive patients with type 2 diabetes in a randomized noninferiority trial.

BACKGROUND: Insulin initiation and optimization is a challenge for patients with type 2 diabetes. Our objective was to determine whether safety and efficacy of AIR inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) using a simplified regimen was noninferior to an intensive regimen. METHODS: This was an open-label, randomized study in insulin-naive adults not optimally controlled by oral antihyperglycemic medications. Simplified titration included a 6 U per meal AIR insulin starting dose. Individual doses were adjusted at mealtime in 2-U increments from the previous day's four-point self-monitored blood glucose (SMBG) (total < or =6 U). Starting Air insulin doses for intensive titration were based on fasting blood glucose, gender, height, and weight. Patients conducted four-point SMBG daily for the study duration. Insulin doses were titrated based on the previous 3 days' mean SMBG (total < or =8 U). RESULTS: End point hemoglobin A1C (A1C) was 7.07 +/- 0.09% and 6.87 +/- 0.09% for simplified (n = 178) and intensive (n = 180) algorithms, respectively. Noninferiority between algorithms was not established. The fasting blood glucose (least squares mean +/- standard error) values for the simplified (137.27 +/- 3.42 mg/dL) and intensive (133.13 +/- 3.42 mg/dL) algorithms were comparable. Safety profiles were comparable. The hypoglycemic rate at 4, 8, 12, and 24 weeks was higher in patients receiving intensive titration (all P < .0001). The nocturnal hypoglycemic rate for patients receiving intensive titration was higher than for those receiving simplified titration at 8 (P < 0.015) and 12 weeks (P < 0.001). CONCLUSIONS: Noninferiority between the algorithms, as measured by A1C, was not demonstrated. This finding re-emphasizes the difficulty of identifying optimal, simplified insulin regimens for patients.

Screening mammogram utilization in women with diabetes.

OBJECTIVE: To determine whether women with diabetes undergo fewer screening mammograms than matched control subjects. RESEARCH DESIGN AND METHODS: A total of 424 women with diabetes aged 50-75 years who received their primary care from general internists at a large Midwestern multispecialty group practice were retrospectively studied for frequency of mammography from August 1997 to January 2000. Two control subjects without diabetes (n = 845) were matched to each case by age, sex, provider, and date of visit. The main outcome measure was the percentage of subjects undergoing mammography 1 year before and 30 days after an index date, defined as the most recent health care visit after August 1997 and before January 2000. RESULTS: Analysis by conditional logistic regression demonstrated that women with diabetes had significantly lower rates of mammograms than control subjects (78.1 vs. 84.9%, respectively; odds ratio 0.63, P = 0.002). After adjusting for insurance status and race, women with diabetes continued to have significantly lower rates of mammography (odds ratio 0.70, P = 0.027). CONCLUSIONS: Women with diabetes were significantly less likely to undergo screening mammography than control subjects. Considering the increasing incidence of diabetes and the equal incidence of malignancy in women with and without diabetes, it would be beneficial to improve breast cancer screening in this population.

Lack of an association between alleles of interleukin-1 alpha and interleukin-1 receptor antagonist genes and Graves' disease in a North American Caucasian population.

Although an association between the human leukocyte antigen (HLA) allele DR3 and Graves' disease (GD) is well documented, the potential role of non-HLA-linked alleles in susceptibility to GD is an area of active investigation. In an attempt to study the potential role of two non-HLA susceptibility alleles in GD and Graves' ophthalmopathy, we examined 286 North American Caucasian individuals (145 normal controls and 141 individuals with GD) for the presence of the A2 allele of the interleukin-1 (IL-1) receptor antagonist gene. In addition, we examined a subset of this population (83 normal controls and 89 individuals with GD) for a specific polymorphism within exon 5 of the IL-1 alpha gene. We found the A2 allelic frequencies (0.25 and 0.23, respectively) and carriage rates (43% and 41%, respectively) in the two groups to be nearly identical. However, findings in the subgroup of patients with the extrathyroidal manifestations of GD (Graves' ophthalmopathy, pretibial dermopathy, and acropachy) suggested a trend toward a higher prevalence of the A2 allele in patients with more severe disease. The allelic frequency (0.28) and carriage rate (47%) of the IL-1 alpha exon 5 polymorphism in individuals with GD were nearly identical to those of the control population (0.28% and 45%, respectively). In summary, we were unable to demonstrate an association between these alleles and GD in our study population. We conclude that neither the A2 allele of the IL-1 receptor antagonist gene nor the IL-1 alpha exon 5 polymorphism confers increased susceptibility to GD.

Pulmonary carcinogenicity of relatively low doses of beta-particle radiation from inhaled 144CeO2 in rats.

This study was conducted to examine the carcinogenic effects of inhaled beta-particle-emitting radionuclides, particularly in lower dose regions in which there were substantial uncertainties associated with available information. A total of 2751 F344/N rats (1358 males and 1393 females) approximately 12 weeks of age at exposure were used. Of these, 1059 rats were exposed to aerosols of 144CeO2 to achieve mean desired initial lung burdens (ILBs) of 18 kBq (low level), 247 rats to achieve mean ILBs of 60 kBq (medium level) and 381 rats to achieve mean ILBs of 180 kBq (high level). Control rats (total of 1064) were exposed to aerosols of stable CeO2. Based on the 95% confidence intervals of the median survival times and the cumulative survival curves, there were no significant differences in the survival of groups of female and male exposed rats relative to controls. The mean lifetime beta-particle doses to the lungs of the rats in the four groups were: low level, 3.6 +/- 1.3 (+/-SD) Gy; medium level, 12 +/- 4.5 Gy; and high level, 37 +/- 5.9 Gy. The crude incidence of lung neoplasms increased linearly with increasing doses to the lungs (controls, 0.57%; low level, 2.0%; medium level, 6.1%; and high level, 19%). The estimated linear risk coefficients for lung neoplasms per unit of dose to the lung were not significantly different for the three dose levels studied. The risk coefficient at the lower level was 39 +/- 14 (+/-SE) excess lung neoplasms per 10(4) rat Gy; at the medium level the risk was 47 +/- 12; and at the higher level the risk was 50 +/- 9.0. The relationship of beta-particle dose to the lung and the crude incidence of lung neoplasms was described adequately by a linear function. We concluded that the risk of lung neoplasms in rats per unit of radiation dose did not increase with decreasing mean beta-particle dose to the lung over the range of 3.6 to 37 Gy. The weighted average of these three values was 47 +/- 6.4 (+/-SE) excess lung neoplasms per 10(4) rat Gy. To extend the risk coefficients for lung neoplasms to lower doses by experimentation will require much larger numbers of rats than used in this study.

Multivariate analysis of HLA loci in conjunction with a thyrotropin receptor codon 52 polymorphism in conferring risk of Graves' disease.

Recent reports have suggested that the HLA alleles DRB3*0101 or DQA1*0501 confer greater susceptibility to Graves' disease than does the DR3 allele. We have reported previously that a non-HLA-linked allele, a polymorphism in codon 52 of the human thyrotropin receptor gene, is highly associated with Graves' disease in females. To determine which of these four susceptibility alleles confers greater independent risk for the development of Graves' disease, we analyzed the alleles in 134 North American Caucasian females who have Graves' disease (n = 69) or are normal controls (n = 65) in a logistic regression model. While we found each of these alleles to be associated with Graves' disease when analyzed independently (corrected p < 0.01 for each of 4 alleles tested), only DR3 (p = 0.0001) and the thyrotropin receptor polymorphism (p = 0.0060) maintained a statistically significant independent association when assessed in conjunction with each of the other alleles in a logistic model. We conclude that DR3 confers the greatest susceptibility to Graves' disease (odds ratio = 7.6) of the alleles within the HLA locus, and that any association between DRB3*0101 or DQA1*0501 and Graves' disease may be a result of the tight linkage disequilibrium between these alleles and DR3. In addition, we found the non-HLA-linked thyrotropin receptor codon 52 polymorphism to confer significant independent risk of Graves' disease (odds ratio = 9.0). Further, because 6 of 6 individuals who possessed both DR3 and the thyrotropin receptor polymorphism had Graves' disease, while no individual in the normal control group possessed both alleles, study of a larger population to assess the potential synergism between these 2 alleles is warranted.

Lack of an independent association between the human leukocyte antigen allele DQA1*0501 and Graves' disease.

The association between the human leukocyte antigen (HLA) serotype DR3 and Graves' disease (GD) in Caucasian populations is well known. However, an even stronger association has been reported recently, especially in the male population, between the closely linked HLA allele DQA1*0501 and GD. We postulated that the reported association between DQA1*0501 and GD may be a result of the linkage of this allele with DR3 and may not represent an independent association. Accordingly, we screened a population of North American Caucasians (n = 218), including patients with GD (n = 101, 32 males, 69 females) and individuals with documented normal thyroid function (n = 117, 51 males, 66 females), for the presence of the DQA1*0501 allele and those alleles corresponding to the DR3 serotype (DRB1*03). Screening was accomplished using sequence specific PCR. A significant association was documented in the total study population between DR3 positivity and GD (P = 0.0002), but not between DQA1*0501 positivity and GD (P = 0.06). After gender stratification, significant associations were found only in the female population (DR3, P = 0.0004; DQA1*0501, P = 0.012) and not in the male population (DR3, P = 1.0; DQA1*0501, P = 1.0). Additionally, in those DR3 negative female subjects (n = 100), there was no independent association between DQA1*0501 positivity (n = 26) and GD (p = 0.82). P-values were corrected, where appropriate, for gender stratification and/or the number of HLA alleles tested. In conclusion, our results demonstrate a lack of independent association between the presence of the HLA allele DQA1*0501 and GD. We suggest that the apparent association between this allele and GD in the female population may be the result of its' close linkage to DR3.

Normal function in vivo of a homozygotic polymorphism in the human thyrotropin receptor.

We have demonstrated previously and association between a polymorphism in the human thyrotropin receptor gene and an increased prevalence of autoimmune thyroid disease in individuals bearing this polymorphic allele. The polymorphism involves the nucleotide base substitution of a cytosine for the wild-type adenine at the first position of codon 52 and is found generally in the heterozygotic state. Such change results in the substitution of a threonine for the wild-type proline at this position in the receptor protein sequence. The resulting protein would lack a beta turn (at position 52) in a potential loop conformation, and thus would have a significantly altered three-dimensional conformation. The biologic consequences of this conformational change in the receptor are unknown, but may involve altered function or immunogenicity. We report here two individuals with normal thyroid function who are homozygous for the thyrotropin receptor polymorphism, suggesting that the altered receptor is able to respond normally to thyrotropin with respect to the maintenance of the euthyroid state.

A polymorphism in the extracellular domain of the thyrotropin receptor is highly associated with autoimmune thyroid disease in females.

We and others have described previously a polymorphism at the first position of codon 52 (C52 --> A52) of the human thyrotropin receptor (hTSHr) gene. To determine its potential significance, we studied female (n = 100) and male (n = 25) patients with autoimmune thyroid disease (Graves' disease, n = 91; Hashimoto's thyroiditis, n = 34) and normal individuals [n = 121, female (n = 69), male (n = 52)]. Screening was performed using AciI restriction enzyme digestions of PCR-amplified genomic DNA. All codon 52 polymorphisms were verified by direct DNA sequencing. Data were analyzed using Chi-square or Fisher exact tests and p-values were corrected for multiple comparisons. Our studies demonstrated that this polymorphism is highly associated with autoimmune thyroid disease in the female population (corrected p = 0.008). We found no such association in the male population. Within females, there was a greater association between Graves' disease and the polymorphism (corrected p = 0.017) than between Hashimoto's thyroiditis and the polymorphism (corrected p = 0.090). The polymorphism was present in a higher proportion of Graves' disease patients with Graves' ophthalmopathy and pretibial dermopathy (40%) or Graves' ophthalmopathy, pretibial dermopathy, and acropachy (60%), than in patients with Graves' disease alone (15%), or Graves' disease and Graves' ophthalmopathy alone (17%). In conclusion, a polymorphism (C52 --> A52) of the hTSHr is associated with autoimmune thyroid disease in females.

The acute toxicity of inhaled beryllium metal in rats.

We exposed rats once by nose only for 50 min to a mean concentration of 800 micrograms/m3 of beryllium metal (initial lung burden, 625 micrograms) to characterize the acute toxic effects within the lung. Histological changes within the lung and enzyme changes within bronchoalveolar lavage (BAL) fluid were evaluated at 3, 7, 10, 14, 31, 59, 115, and 171 days postexposure (dpe). Beryllium metal-exposed rats developed acute, necrotizing, hemorrhagic, exudative pneumonitis and intraalveolar fibrosis that peaked at 14 dpe. By 31 dpe, inflammatory lesions were replaced by minimal interstitial and intraalveolar fibrosis. Necrotizing inflammation was observed again at 59 dpe which progressed to chronic-active inflammation by 115 dpe. This inflammation worsened progressively, as did alveolar macrophage and epithelial hyperplasia, becoming severe at 171 dpe. Low numbers of diffusely distributed lymphocytes were also present but they were not associated with granulomas as is observed in beryllium-induced disease in man. Throughout the experiment, total numbers of cells were elevated within the BAL samples due primarily to increased numbers of neutrophils. Lymphocytes were not elevated in BAL samples collected from beryllium-exposed rats at any time after exposure. Lactate dehydrogenase (LDH), beta-glucuronidase, and protein levels were elevated in BAL fluid from 3 through 14 dpe but returned to near normal levels by 31 dpe. LDH increased once again at 59 dpe and remained elevated at 171 dpe. beta-Glucuronidase and protein levels were slightly, but not significantly, elevated from 31 through 171 dpe. Results indicate that inhalation of beryllium metal by rats results in severe, acute chemical pneumonitis that is followed by a quiescent period of minimal inflammation and mild fibrosis. Progressive, chronic-active, fibrosing pneumonitis is observed later. Chronic beryllium lung disease of man is an immunologically mediated granulomatous lung disease, whereas beryllium-induced lung lesions in rats appear to be due to direct chemical toxicity and foreign-body-type reactions.

The induction of chromosome damage in CHO cells by beryllium and radiation given alone and in combination.

Studies were conducted to determine the effects of BeSO4 or X rays, alone and in combination, on cell cycle kinetics, cell killing, and the production of chromosome aberrations in Chinese hamster ovary (CHO) cells. The concentration of BeSO4 required to kill 50% of CHO cells exposed to BeSO4 for 20 h was determined to be 1.1 mM with 95% confidence intervals of 0.72 to 1.8 mM. During the last 2 h of the 20-h beryllium treatment (0.2 and 1.0 mM), cells were exposed to 0.0, 1.0, or 2.0 Gy of X rays. Exposure to either BeSO4 or X rays produced a change in cell cycle kinetics which resulted in an accumulation of cells in the G2/M stage of the cell cycle. However, combined exposure to both agents resulted in a block similar to that observed following exposure to X rays only. The background level of chromosome damage was 0.05 +/- 0.015 aberrations/cell in the CHO cells. Seven hours after the end of exposure to 0.2 and 1.0 mM beryllium, 0.03 +/- 0.003 and 0.09 +/- 0.02 aberrations/cell, respectively, were observed. The data for chromosome aberrations following X-ray exposure were fitted to a linear model with a coefficient of 0.14 +/- 0.01 aberrations/cell/Gy. When beryllium was combined with the X-ray exposure the interactive response was predicted by a multiplicative model and was significantly higher (P less than 0.05) than predicted by an additive model. The influence of time after radiation exposure on the interaction between beryllium and X rays was also determined. No interaction between beryllium and X-ray exposure in the induction of chromosome-type aberrations (P greater than 0.05) was detected. The frequency of chromatid-type exchanges and total aberrations was significantly higher (P less than 0.05) in the radiation plus beryllium-exposed cells when compared to cells exposed to X rays only, at both 9 and 12 h after X-ray exposure. These data suggest that the multiplicative interaction may be limited to cells in the S and G2 stages of the cell cycle.

The current approach of the ICRP Task Group for modeling doses to respiratory tract tissues.

For radiation protection purposes, the International Commission on Radiological Protection (ICRP) Task Group proposes to apportion radiation risk within the respiratory tract according to the tumor mortality rates observed in the different anatomical regions. This approach requires that doses absorbed by extrathoracic tissues must be considered, in addition to those in the lung. For the extrathoracic region, the tissues at highest potential risk are the pharyngeal parts of the nasopharynx and oropharynx and a part of the larynx. In the lung, all tissues are potentially at risk, and it is necessary to consider doses absorbed by bronchial tissues, the lung parenchyma, and lymph nodes. This paper outlines the methods proposed by the Task Group to evaluate the heterogeneous doses absorbed by sensitive cells in these tissues from radioactive decays of alpha-emitters. The objective is to evaluate doses to broad regions of the respiratory tract, where the regions are defined to reflect substantial differences in potential risk when taking into account deposition and clearance behavior. The Task Group proposes to represent the respiratory tract by three generic regions: an extrathoracic region and two thoracic regions, one clearing fast and one slowly. The models of aerosol deposition and clearance applied for each region are outlined. To illustrate the use of the model, doses are evaluated for the key cases of short-lived radionuclides and long-lived insoluble alpha-emitters and are discussed with regard to current ICRP recommendations.

Modeling accumulations of particles in lung during chronic inhalation exposures that lead to impaired clearance.

Chronic inhalation of insoluble particles of low toxicity that produce substantial lung burdens of particles, or inhalation of particles that are highly toxic to the lung, can impair clearance. This report describes model calculations of accumulations in lung of inhaled low-toxicity diesel exhaust soot and high-toxicity Ga2O3 particles. Lung burdens of diesel soot were measured periodically during a 24-mo exposure to inhaled diesel exhaust at soot concentrations of 0, 0.35, 3.5, and 7 mg m-3, 7 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y after a 4-wk exposure to 23 mg Ga2O3 m-3, 2 h d-1, 5 d wk-1. Lung burdens of Ga2O3 were measured for 1 y both studies using inhaled radiolabeled tracer particles. Simulation models fit the observed lung burdens of diesel soot in rats exposed to the 3.5- and 7-mg m-3 concentrations of soot only if it was assumed that clearance remained normal for several months, then virtually stopped. Impaired clearance from high-toxicity particles occurred early after accumulations of a low burden, but that from low-toxicity particles was evident only after months of exposure, when high burdens had accumulated in lung. The impairment in clearances of Ga2O3 particles and radiolabeled tracers was similar, but the impairment in clearance of diesel soot and radiolabeled tracers differed in magnitude. This might have been related to differences in particle size and composition between the tracers and diesel soot. Particle clearance impairment should be considered both in the design of chronic exposures of laboratory animals to inhaled particles and in extrapolating the results to people.