Risk Of Lung Tumors Research Articles

Modeling arsenic in European topsoils with a coupled semiparametric (GAMLSS-RF) model for censored data

Arsenic (As) is a versatile heavy metalloid trace element extensively used in industrial applications. As is carcinogen, poses health risks through both inhalation and ingestion, and is associated with an increased risk of liver, kidney, lung, and bladder tumors. In the agricultural context, the repeated application of arsenical products leads to elevated soil concentrations, which are also affected by environmental and management variables. Since exposure to As poses risks, effective assessment tools to support environmental and health policies are needed. However, the most comprehensive soil As data available, the Land Use/Cover Area frame statistical Survey (LUCAS) database, contains severe limitations due to high detection limits. Although within International Organization for Standardization standards, the detection limits preclude the adoption of standard methodologies for data analysis. The present work focused on developing a new method to model As contamination in European soils using LUCAS soil samples. We introduce the GAMLSS-RF model, a novel approach that couples Random Forests with Generalized Additive Models for Location, Scale, and Shape. The semiparametric model can capture non-linear interactions among input variables while accommodating censored and non-censored observations and can be calibrated to include information from other campaign databases. After fitting and validating a spatial model, we produced European-scale As concentration maps at a 250 m spatial resolution and evaluated the patterns against reference values (i.e., two action levels and a background concentration). We found a significant variability of As concentration across the continent, with lower concentrations in Northern countries and higher concentrations in Portugal, Spain, Austria, France and Belgium. By overcoming limitations in existing databases and methodologies, the present approach provides an alternative way to handle highly censored data. The model also consists of a valuable probabilistic tool for assessing As contamination risks in soils, contributing to informed policy-making for environmental and health protection.

Association between TGF-β1 rs1982073/rs1800469 polymorphism and lung cancer susceptibility: An updated meta-analysis involving 7698 cases and controls.

Background:There have been several case–control studies to assess the relationship between the transforming growth factor-β1 (TGF-β1) T + 869C (rs1982073)/C-509T (rs1800469) gene polymorphism and lung cancer in recent years; however, the results remain controversial. In this study, we investigated the potential correlation between the TGF-β1 T + 869C/C-509T polymorphism and increased risk of lung cancer through meta-analysis.Methods:We searched the Cochrane Library database, Embase, PubMed, Web of Science, China National Knowledge Infrastructure, and the Wanfang Data Information Service platform to identify relevant case–control studies in strict accordance with the inclusion and exclusion criteria. The odds ratio (OR) and its 95% confidence interval (95% CI) were used to evaluate the correlation between TGF-β1 gene polymorphism and lung tumor risk. Sensitivity analysis and Egger test were used to evaluate the stability of the results and possible publication bias.Results:A total of 8 studies, with 3680 patients and 4018 controls, were included. The meta-analysis revealed that there was no conspicuous correlation between the TGF-β1 T + 869C (rs1982073)/C-509T (rs1800469) variant and lung cancer in the overall population. For TGF-β1 C-509T, a significant decreased risk was identified in patients with nonsmall-cell lung cancer (NSCLC) in the analysis stratified by disease (TT vs CT + CC: P = .02, OR = 0.49, 95% CI 0.27–0.90). However, for TGF-β1 T + 869C, subgroup analysis showed no correlation between the T + 869C polymorphism and lung cancer susceptibility in patients with NSCLC. In the subgroup analysis by ethnicity, no distinct association was observed between T + 869C (rs1982073)/C-509T (rs1800469) polymorphism and lung cancer susceptibility in the Asian and Caucasian groups. Moreover, no significant association was found in the analysis of groups stratified by age, sex, and smoking history.Conclusion:The TGF-β1 T + 869C (rs1982073) and C-509T (rs1800469) polymorphisms are not implicated in lung cancer susceptibility in the overall population. However, our analysis indicated that the C-509T (rs1800469) polymorphism decreases the risk of lung cancer in patients with NSCLC.

A combined experimental and numerical study on upper airway dosimetry of inhaled nanoparticles from an electrical discharge machine shop

BackgroundsExposure to nanoparticles in the workplace is a health concern to occupational workers with increased risk of developing respiratory, cardiovascular, and neurological disorders. Based on animal inhalation study and human lung tumor risk extrapolation, current authoritative recommendations on exposure limits are either on total mass or number concentrations. Effects of particle size distribution and the implication to regional airway dosages are not elaborated.MethodsReal time production of particle concentration and size distribution in the range from 5.52 to 98.2 nm were recorded in a wire-cut electrical discharge machine shop (WEDM) during a typical working day. Under the realistic exposure condition, human inhalation simulations were performed in a physiologically realistic nasal and upper airway replica. The combined experimental and numerical study is the first to establish a realistic exposure condition, and under which, detailed dose metric studies can be performed. In addition to mass concentration guided exposure limit, inhalation risks to nano-pollutant were reexamined accounting for the actual particle size distribution and deposition statistics. Detailed dosimetries of the inhaled nano-pollutants in human nasal and upper airways with respect to particle number, mass and surface area were discussed, and empirical equations were developed.ResultsAn astonishing enhancement of human airway dosages were detected by current combined experimental and numerical study in the WEDM machine shop. Up to 33 folds in mass, 27 folds in surface area and 8 folds in number dosages were detected during working hours in comparison to the background dosimetry measured at midnight. The real time particle concentration measurement showed substantial emission of nano-pollutants by WEDM machining activity, and the combined experimental and numerical study provided extraordinary details on human inhalation dosimetry. It was found out that human inhalation dosimetry was extremely sensitive to real time particle concentration and size distribution. Averaged particle concentration over 24-h period will inevitably misrepresent the sensible information critical for realistic inhalation risk assessment.ConclusionsParticle size distribution carries very important information in determining human airway dosimetry. A pure number or mass concentration recommendation on the exposure limit at workplace is insufficient. A particle size distribution, together with the deposition equations, is critical to recognize the actual exposure risks. In addition, human airway dosimetry in number, mass and surface area varies significantly. A complete inhalation risk assessment requires the knowledge of toxicity mechanisms in response to each individual metric. Further improvements in these areas are needed.

Primary Particles and Their Agglomerate Formation as Modifying Risk Factors of Nonfibrous Nanosized Dust

The incidence of certain cancers correlates with the number of dust particles in the air. Nanosized particles differ from coarser particles by their increasing tendency to form agglomerates. The dissociation of biodurable agglomerates after deposition in the alveolar region resulted in a higher toxic potential. Biodurable dusts in the urban and workplace environment were analyzed to determine an effect-relevant exposure parameter. The characterization of the dusts relating to their number of primary particles (Pp) and agglomerates and aggregates (A + A) was performed by electron microscopy. Diesel soot, toner material, and seven further dust samples in the workplace environment are composed of high numbers of nanosized primary particles (<100 nm) per unit mass occurring as larger agglomerates. Primary particles of rock, kaoline, and seven further dusts sampled in the workplace are not nanosized. In a multivariate analysis that predicted lung tumor risk, the mass, volume, and numbers of A + A and Pp per milligram dust were shown to be relevant parameters. Dose-response relationships revealed an increased tumor risk in rats with higher numbers of Pp in nanosized dust, which occurs unintentionally in the environment.

Preliminary evaluation of the human relevance of respiratory tumors observed in rodents exposed to naphthalene

Inhalation bioassays in mice and rats exposed to naphthalene (NA) show incidences of lung and nasal cancer, respectively. This paper describes a preliminary mode of action (MOA)/human relevance (HR) framework for NA. Species differences in both carcinogenic and cytotoxic responses between the rodent and human have been noted based on qualitative and quantitative differences in metabolism. Some occur at the initial oxidation of NA in the rat through CYP2F, versus CYP2A13 metabolism in the human respiratory system and which results in a difference in the specific naphthoquinone formed. Normally, subsequent reactive metabolites are then conjugated through glutathione, but high dose exposures, as in the rat bioassay, result in glutathione depletion, and the availability of 1,2-naphthoquinone for other conjugation. In the rat nose, it is proposed that a naphthoquinone imine is formed via a species and site-specific aryl amidase acting on an amino acid conjugate of the quinone. Such a quinone imine is believed to be the active agent in Alachlor and phenacetin, resulting in the same profile of respiratory tumors in the rat as NA. Based on the MOA and the limited epidemiological data indicating no human evidence of nasal or lung tumor risk, the carcinogenic response observed in rats does not appear relevant to the human.

A V141L polymorphism of the human LRMP gene is associated with survival of lung cancer patients

Mouse Lrmp and Casc1 genes are candidates for the pulmonary adenoma susceptibility 1 (Pas1) locus, the major determinant of strain variation in lung tumor susceptibility. These genes contain coding and non-coding single nucleotide polymorphisms (SNPs) strongly associated with lung tumor risk in mice. Analysis of LRMP and CASC1 gene SNPs in 361 lung adenocarcinoma (ADCA) patients and 327 healthy controls revealed common SNPs in LRMP (V141L and S197C) and CASC1 (R33S and three intronic variations), and none showed a significant association with lung ADCA risk. However, in the time-dependent Cox regression model, after adjustment for age, gender, smoking history and clinical stage, the carrier status of the Leu variation (V141L) of the LRMP gene was associated with higher mortality in patients with age at tumor onset < or = 65 years [hazard ratio (HR) 2.3; 95% CI 1.4-3.7; P = 0.001]. These findings suggest that the LRMP V141L polymorphism can predict survival in lung ADCA and that the role of LRMP and CASC1 in human lung cancer risk may differ from that in mice.

Carcinogenicity of radon/radon decay product inhalation in rats – effect of dose, dose rate and unattached fraction

Purpose: The effects of inhalation of radon/radon decay products at different total doses, dose rates and ‘unattached’ fractions were investigated in a life span study in rats.Materials and methods: 1574 rats inhaled radon/radon decay products in a purpose-built recirculating exposure system that provided stable/reproducible exposure conditions. 501 were maintained as controls.Results: Lung tumour incidences were significantly elevated in most exposed groups. The study power was insufficient to resolve the shape of the dose and dose rate response curves, but combination of this data with that from other studies demonstrated that for high cumulative exposures, the lifetime excess absolute risk increases with increasing exposure durations and for low cumulative exposures the opposite trend occurs. Exposure did not increase leukaemia incidences. A small number of non-lung tumour types including mammary fibroadenoma showed elevated incidences in some exposed groups, however not consistently across all exposure groups and showed no dose or dose rate relationship.Conclusions: Radon/radon decay product exposure caused excess lung tumours in rats along with limited non-lung effects. The results are consistent with the findings that at low cumulative exposures decreasing exposure concentrations or protracting the time over which the dose is delivered, reduces lung tumour risk. At higher levels, decreasing exposure concentrations or protracting exposure time increases lung tumour risk.

Mechanistic modelling in large case-control studies of lung cancer risk from smoking.

The two-step clonal expansion (TSCE) model is applied to large case-control studies, frequency matched for age, which allow estimation of the RR of lung tumour risk caused by smoking. For estimating background hazard rates, mortality data from the study areas are used to supplement the case-control data. Two approaches are used to analyse the data, based on the unconditional and the conditional likelihoods. They are demonstrated to give nearly identical results. Some model diagnostics are performed and demonstrate a good model fit. Our results indicate that smoking acts on the promotion and transformation parameters, but not on the initiation parameter of the TSCE model. The fitted relative risk of current smokers peaks between ages 50 and 60 years. The relative risk of male ex-smokers decreases strongly with time since end of exposure, but does not reach the risk of non-smokers, and does not decrease as much as for female ex-smokers.

Lung-specific expression of dominant-negative mutant p53 in transgenic mice increases spontaneous and benzo(a)pyrene-induced lung cancer.

Mutations in the p53 gene have been implicated to play an important role in the development of various human cancers. To evaluate the importance of p53 in lung cancer, a transgenic mouse model was established by utilizing the Clara cell secretory protein (CCSP) promoter to target the expression of a dominant-negative mutant form of p53 (dnp53) in the lung. In two transgenic CCSP-dnp53 founder lines, the dnp53 protein was expressed exclusively in the lungs. The incidence of spontaneous lung cancer in 18-month-old transgenic mice was 45%, whereas that in age-matched control mice was 20%. The relative risk of lung tumors in CCSP-dnp53 mice was 2.3 times that of wild-type mice (exact confidence limits of 0.69, 17.5). In addition to the increased incidence of spontaneous lung tumor, these mice were more susceptible to the development of lung adenocarcinoma after exposure to benzo(a)pyrene (BaP). Six months after intratracheal instillation of benzo(a)pyrene, the tumor incidence in wild-type and CCSP-dnp53 mice was 39% and 73%, respectively. The risk of lung tumors was 25.3 times greater in BaP-treated mice adjusted for transgene expression (95% confidence limits of 3.29, 678, mid-p corrected). These results suggest that p53 function is important for protecting mice from both spontaneous and BaP-induced lung cancers.

Lung tumors in A/J mice exposed to environmental tobacco smoke: estimated potency and implied human risk.

Directly inhaled tobacco smoke is a recognized human lung carcinogen, and epidemiological studies suggest relative risks of about 1.2-1.4 for nonsmoking spouses of smokers typically exposed to environmental tobacco smoke (ETS). While many individual ETS components have been shown experimentally to induce lung tumors, ETS itself was only recently shown to induce lung tumors in a series of studies in which strain A/J mice were exposed to well-defined ETS atmospheres. Data from these studies indicate that ETS exposure clearly can increase combined malignant and benign lung tumors in multiple experiments involving male and female A/J mice, and thus provide convincing evidence that ETS is a positive mouse carcinogen. Tumorigenic potencies estimated from these A/J mouse bioassay data predict a corresponding range of increased human risk (0.2-0.5%) that overlaps that implied by case-control studies showing increased lung cancer risks in lifelong nonsmokers married to smokers. In A/J mice exposed to a significantly tumorigenic ETS concentration, lung tumors were found to be significantly smaller than those in corresponding control mice, and mice so exposed for 9 months had significantly fewer tumors/animal than mice exposed for 5 months followed by 4 months in filtered ETS-free air. These findings support hypotheses that ETS does not promote growth of spontaneous neoplastic foci in A/J mice, and that ETS-induced lung-tumor risk in A/J mice occurs predominantly by genotoxic effects that can be suppressed by reduced cell proliferation associated with chronic, high-level ETS exposure. The results obtained add to evidence that A/J mouse lung tumors induced by ETS provide a relevant biological model of ETS-induced human lung tumors.

Modelling lung tumour risk in radon-exposed uranium miners using generalizations of the two-mutation model of Moolgavkar, Venzon and Knudson

Purposes : To model radon-induced lung cancer in uranium miners using a quasi-biological model of carcinogenesis. Materials and methods : Fitting of generalizations of the stochastic two-mutation carcinogenesis model of Moolgavkar, Venzon and Knudson to a case-control dataset nested within the cohort and to the full cohort of lung cancer mortality in the Colorado Plateau uranium miners, taking account of exposure to cigarette smoke and to radon daughters. Results : Models with three mutations gave adequate descriptions of the time and age patterns of radon-daughter-induced excess lung tumour mortality. The overall fit of the two-mutation model to the case-control data was somewhat worse than that of the three-mutation model. For both the optimal two- and threemutation models radon daughters and cigarette smoke were assumed to act on the first mutation rate. In the optimal twomutation model, radon daughters also modified the intermediate cell death or differentiation rate. In the optimal three-mutation model, radon daughters modified the second mutation rate. In all models, the action of radon daughters and cigarette smoke was markedly non-linear, particularly in their action on the mutation rates. The optimal two- and three-mutation models fitted to the cohort data were of slightly different form to those fitted to the case-control data. The model fits to the cohort data are preferred to those to the case-control data on grounds of plausibility. Conclusions : Quasi-biological carcinogenesis models with three mutations give adequate descriptions of the time and age patterns of radon-daughter-induced excess lung tumour mortality. The overall fit of the two-mutation model is somewhat worse than that of the three-mutation model.

Pulmonary inflammation in rats after intratracheal instillation of quartz, amorphous SiO 2, carbon black, and coal dust and the influence of poly-2-vinylpyridine-N-oxide (PVNO)

Effects of poly-2-vinylpyridine-N-oxide (PVNO) were investigated in numerous in vivo and in vitro studies published in the nineteen sixties and seventies. These studies showed that PVNO inhibited development of fibrosis from quartz dust and improved lung clearance of quartz after inhalation exposure. Ameliorating effects of PVNO were observed also for pulmonary damage from colloidal SiO2 and organic substances, and the fibrogenic inflammation caused by carrageenan. Although it is not proven that silicosis is a precondition for quartz-induced lung tumours, we investigated the hypothesis that PVNO could reduce the lung tumour risk from quartz in rats. A carcinogenicity study was therefore started in rats with the main focus on the quantitative relationships among pulmonary inflammation, fibrosis and neoplasia caused by intratracheal instillation of 3 mg quartz DQ 12 with or without additional subcutaneous PVNO treatment. Other study groups were treated with multiple dust instillations, i.e. 30 instillations of 0.5 mg amorphous SiO2 at intervals of 2 weeks, 10 instillations of 0.5 mg of ultrafine carbon black or 1 mg coal at weekly intervals. The analyses of the bronchoalveolar lavage fluid (BALF) 9 months after start of the life-time study showed that the aim of producing similar levels of increased enzyme concentrations in the four groups treated with quartz/PVNO, amorphous SiO2, carbon black and coal was achieved. A 2.5- to 7.7-fold increase for lactate dehydrogenase (LDH), total protein, alkaline phosphatase and gamma-glutamyl transferase (gamma-GT) was found in these groups as compared to the control. In contrast, quartz treatment without PVNO increased the LDH level up to 24-fold and of total protein to 13-fold. However, the cell counts in the BALF were not so much different in all five groups, i.e. quartz without PVNO (leukocytes: 480.000, PMN: 190.000), quartz with PVNO (leukocytes: 300.000, PMN: 100.000), amorphous SiO2 (leukocytes: 570.000, PMN: 315.000), carbon black (leukocytes: 390.000, PMN: 150.000) and coal (leukocytes: 200.000, PMN: 65.000). Histopathological investigations after four weeks and three months revealed that the used PVNO sample was active in the quartz and amorphous SiO2 groups and markedly reduced the incidences or severity of several pulmonary changes such as macrophage accumulation, inflammatory cell infiltration, interstitial fibrosis, bronchiolo-alveolar hyperplasia, alveolar lipoproteinosis and amorphous SiO2 -induced granulomatous alveolitis/interstitial fibrotic granulomas. Also in the lung-associated lymph nodes (LALN), PVNO treatment significantly reduced the incidence and severity of inflammation in both quartz and amorphous SiO2 groups as evidenced by the presence of well-circumscribed aggregates of intact particle-laden macrophages without signs of degeneration and accompanying granulocytic infiltration and fibrosis. Immunological investigations at the 9 months timepoint on the in vitro production of reactive nitrogen (RNI) or oxygen (ROI) intermediates and tumour necrosis factor (TNF-alpha) from BALF-derived cells indicated a diminished responsiveness to LPS in all particle treatment groups. A diminished production of ROI was also found in the quartz, carbon black, and coal dust groups, respectively, as compared to the values seen in the quartz/PVNO- and amorphous SiO2 treated groups. Treatment with quartz plus PVNO restored the capability of the cells to respond to LPS as compared to the treatment with quartz alone. TNF-alpha production was diminished in the groups treated with quartz, carbon black, and coal dust alone whereas in the quartz/PVNO- and amorphous SiO2-treated groups an elevated TNF-alpha production was seen. These results led to the conclusion that only amorphous SiO2 did not affect the "normal" ability of the cells to respond to LPS and that PVNO protected the cells from a toxic effect of the quartz particles.

Occupational cancer in Italy.

This article is a discussion of occupational cancer in Italy. The introduction provides the necessary context of Italian industrialization and occupational health regulation. This is followed by a review of Italian epidemiologic studies of occupational cancer risks considered in terms of relative measures of risk and attributable risk of carcinogenic agents or exposure circumstances. We attempt to establish the number of workers exposed to carcinogens in Italy and the intensity of their exposures. Finally, the Italian system of compensation for occupational cancer is discussed. Several cohort and case-control studies have addressed the issue of occupational risks, mostly among male workers. The results of these studies suggest that the growing incidence of and mortality by mesothelioma is explained by the widespread and intense exposure to asbestos in some Italian industrial settings. A high attributable risk of lung tumors among male populations in industrial areas of northern Italy is explained by occupational exposures. However, insufficient data are available for clear definition of the extent and intensity of occupational exposure to carcinogenic substances. In Italy, we must prioritize and maximize resources in occupational cancer epidemiology and revitalize the role of national institutions. Recent legislation has established new regulations on the handling of carcinogenic substances in industrial settings, a new list of occupational diseases, and a national registry of mesothelioma linked to asbestos exposure. These legislative changes are expected to have positive effects.

Occupational Cancer in Italy

The paper is a discussion of occupational cancer in Italy. The introductory section provides the necessary context of Italian industrialization and occupational health regulation. This is followed by a review of Italian epidemiological studies of occupational cancer risks, considered in terms of relative measures of risk and Attributable Risk to carcinogenic agents or exposure circumstances. A section attempts to establish the number of workers who have been exposed to carcinogens in Italy and the intensity of their exposures. Several cohort and case-control studies have addressed the issue of occupational risks, mostly among male workers. The results of these studies suggest that the growing incidence of and mortality by mesothelioma is explained by the widespread and intense exposure to asbestos in some Italian industrial settings. A high Attributable Risk of lung tumors among male populations in industrial areas of northern Italy is explained by occupational exposures. However, insufficient data are available for the clear definition of the extent and intensity of occupational exposure to carcinogenic substances. In Italy, we need to prioritize and maximize resources in occupational cancer epidemiology and to revitalize the role of national institutions. Recent legislation has established new regulations on the handling of carcinogenic substances in industrial settings, a new list of occupational diseases, and a national registry of mesothelioma linked to asbestos exposure. These legislative changes are expected to have positive effects.

Two-Step Model for the Risk of Fatal and Incidental Lung Tumors in Rats Exposed to Radon

Data from 4276 rats with radon exposures up to 10,000 WLM at rates up to 1000 WL are analyzed with a two-step clonal expansion model. The age dependences of the hazard for the risks for fatal and for incidental tumors are very different. Therefore, two different parameterizations of the model are used in the two cases. In both cases radiation acts only on the initiating mutation and the clonal expansion, but not on the second mutation. Average exposure rates of 5 WL for fatal tumors and 0.5 WL for incidental tumors double the rate of spontaneous mutations. While the fatal tumors show a linear increase in the effective clonal expansion rate up to about 100 WL average exposure rate and a saturation at higher exposure rates, the incidental tumors follow a step-like behavior of this parameter. It is proposed that only the fatal lung tumors among the rats be used for generalizations to models for lung cancer in humans. The fitted model for fatal tumors shows an inverse dose-rate effect at average exposure rates above 20 WL. However, below 10 WL the lung cancer risk per unit exposure decreases with increasing duration of exposure. Between 10 and 20 WL, the difference in ERR/WLM between acute and protracted exposure is small.

Inhaled uranium ore dust and lung cancer risk in rats.

Using a nose-only inhalation system, male Sprague-Dawley rats were exposed 4.2 h d(-1), 5 days per week for 65 weeks to one of two concentrations of natural uranium ore dust aerosol (44% U, 50 mg m(-3) and 19 mg m(-3)) without significant radon content. After inhalation exposure ceased, the rats were allowed to live for their natural lifetime. Lung uranium burdens, measured at the time of death of each animal, declined exponentially after dust inhalation ceased, and the rate of decline was independent of the initial lung burden. Lymph node specific burdens ranged from 1 to 60 fold greater than the specific lung burden in the same animal. No lymph node tumors were observed. The frequency of primary malignant lung tumors was 0.016, 0.175 and 0.328 and primary non-malignant lung tumors 0.016, 0.135 and 0.131 in the control, low and high aerosol exposed groups, respectively. There was no difference in tumor latency between the groups. Absorbed dose to the lung was calculated for each animal in the study. The average doses for all the animals exposed to the low and high dust aerosol concentrations were 0.87 Gy and 1.64 Gy respectively, resulting in an average risk of malignant lung tumors of about 0.20 tumors per animal per Gy in both groups. The frequency of primary lung tumors was also calculated as a function of dose increment for both exposed groups individually and combined. The data indicate that, in spite of the above result, lung tumor frequency was not directly proportional to dose. However, when malignant lung tumor frequency was calculated as a function of dose rate (as measured by the lung burden at the end of dust inhalation) a direct linear relationship was seen (p < 0.01) suggesting dose rate may be a more important determinant of lung cancer risk than dose. Conversely, non-malignant lung tumors were significantly correlated with low lung burdens (p = 0.01). We conclude that chronic inhalation of natural uranium ore dust alone in rats creates a risk of primary malignant and non-malignant lung tumor formation and that malignant tumor risk was not directly proportional to dose, but was directly proportional to dose rate.

Chronic cigarette smoke exposure increases the pulmonary retention and radiation dose of 239Pu inhaled as 239PuO2 by F344 rats.

As a portion of a study to examine how chronic cigarette smoke exposure might alter the risk of lung tumors from inhaled 239puO2 in rats, the effects of smoke exposure on alpha-particle lung dosimetry over the life-span of exposed rats were determined. Male and female rats were exposed to inhaled 239PuO2 alone or in combination with cigarette smoke. Animals exposed to filtered air alone served as controls for the smoke exposure. Whole-body exposure to mainstream smoke diluted to concentrations of either 100 or 250 mg total particulate matter m(-3)(LCS or HCS, respectively) began at 6 wk of age and continued for 6 h d(-1), 5d wk(-1), for 30 mo. A single, pernasal, acute exposure to 239PuO2 was given to all rats (control, LCS and HCS) at 12 wk of age. Exposure to cigarette smoke caused decreased body weight gains in a concentration dependent manner. Lung-to-body weight ratios were increased in smoke-exposed rats. Rats exposed to cigarette smoke before the 239PuO2 exposure deposited less 239Pu in the lung than did controls. Except for male rats exposed to LCS, exposure to smoke retarded the clearance of 239Pu from the lung compared to control rats through study termination at 870 d after 239PuO2 exposure. Radiation doses to lungs were calculated by sex and by exposure group for rats on study for at least 360 d using modeled body weight changes, lung-to-body weight ratios, and standard dosimetric calculations. For both sexes, estimated lifetime radiation doses from the time of 239PuO2 exposure to death were 3.8 Gy, 4.4 Gy, or 6.7 Gy for the control, LCS, or HCS exposure groups, respectively. Assuming an approximately linear dose-response relationship between radiation dose and lung neoplasm incidence, approximate increases of 20% or 80% in tumor incidence over controls would be expected in rats exposed to 239PuO2 and LCS or 239PuO2 and HCS, respectively.

Lung Cancer Rates in Carbon-Black Workers Are Discordant with Predictions from Rat Bioassay Data

The recent demonstration of lung tumors in rats chronically exposed to airborne carbon-black particles has prompted reevaluation of the carcinogenicity of carbon black. However, accumulating evidence suggests that rat responses to inhaled particles are unique and are mediated by the sequelae to lung overload conditions. To test the predictive value of the rat inhalation bioassay for human lung cancer risk, we examined epidemiologic studies of workers exposed to carbon black during its manufacture or use. Industries in which significant airborne carbon-black exposure has occurred were not associated with increased lung cancer risk. We also predicted the number of occupational lung cancer cases that one would expect in exposed workers, based on the cancer potency of carbon black derived from rat studies. Our quantitative comparison of the tumorigenicity of carbon black predicted from rat studies to the lung cancer rate in carbon-black workers showed a marked discrepancy between the lung cancers predicted and those actually observed. We found that far more lung cancers are predicted from the rat bioassay than can be demonstrated in workers. We determined that it is highly unlikely that this discrepancy is due to chance. We conclude that extrapolating the incidence of lung tumors in rats inhaling inert, insoluble particles, such as carbon black, to humans must be seriously questioned. Using rat inhalation bioassay data for carbon black to estimate lung tumor risk in humans must be seriously questioned unless the mechanisms of the rat's unique response are shown to be relevant to humans.

Pulmonary Carcinogenicity of Repeated Inhalation Exposure of Rats to Aerosols of 239 PuO 2

To study the long-term biological effects of repeated inhalation exposure to 239PuO2, 84-day-old rats were exposed to aerosols of 239PuO2 to re-establish desired 239Pu lung burdens of 26, 80 or 250 Bq every other month for 1 year (seven exposures). Other rats were exposed once at 84 or 450 days of age to achieve desired initial lung burdens of 30, 90, 280 or 850 Bq. The incidences of lung tumors were not significantly different (Fisher's exact test; P > 0.05) in groups of rats with similar lifetime mean alpha-particle doses to the lungs of 0.90 +/- 0.39 to 4.4 +/- 1.8 (+/- SD) Gy, whether exposed once or repeatedly. Among rats with mean alpha-particle doses of 12 +/- 2.4 to 10 +/- 2.1 Gy to the lungs after single or repeated exposures, respectively, the crude incidence of lung tumors was significantly less (Fisher's exact test; P < 0.05) in the rats exposed repeatedly. Times to death of rats with lung tumors were compared among groups with similar alpha-particle doses to the lungs after single or repeated exposure to 239PuO2. Those that died with lung tumors after repeated exposures died at times similar to (Mantel-Cox statistic; P > 0.05) or later than (Mantel-Cox statistic; P < 0.05) those for 84-day-old rats exposed once. The risk of lung tumors in rats per unit dose to the lungs was less in the rats exposed repeatedly than in those exposed once. It was concluded that alpha-particle doses to the lung of rats exposed repeatedly to aerosols of 239PuO2 were not more carcinogenic and possibly were less carcinogenic than the dose after a single inhalation exposure when rats with similar lifetime alpha-particle doses to the lungs were compared. The relative biological effectiveness in rats of the alpha-particle dose to the lungs from inhaled 239PuO2 relative to beta-particle doses to the lungs from inhaled 144CeO2 was 21 +/- 3.

The Sizes, Shapes, and Mineralogy of Asbestos Structures that Induce Lung Tumors or Mesothelioma in AF/HAN Rats Following Inhalation1

Data from inhalation studies in which AF/HAN rats were exposed to nine different types of asbestos dusts (in 13 separate experiments) are employed in a statistical analysis to determine if a measure of asbestos exposure (expressed as concentrations of structures with defined sizes, shapes and mineralogy) can be identified that satisfactorily predicts the observed lung tumor or mesothelioma incidence in the experiments. Due to limitations in the characterization of asbestos structures in the original studies, new exposure measures were developed from samples of the original dusts that were re-generated and analyzed by transmission electron microscopy using a direct transfer technique. This analysis provided detailed information on the mineralogy (i.e., chrysotile, amosite, crocidolite or tremolite), type (i.e., fiber, bundle, cluster, or matrix), size (length and width) and complexity (i.e., number of identifiable components of a cluster or matrix) of each individual structure. No univariate measure of exposure was found to provide an adequate description of the lung tumor responses observed among the inhalation studies, although the measure most highly correlated with tumor incidence is the concentration of structures > or = 20 microns in length. Multivariate measures of exposure were identified that do adequately describe the lung tumor responses. Structures contributing to lung tumor risk appear to be long (> or = 5 microns) thin (0.4 microns) fibers and bundles, with a possible contribution by long and very thick (> or = 5 microns) complex clusters and matrices. Potency appears to increase with increasing length, with structures longer than 40 microns being about 500 times more potent than structures between 5 and 40 microns in length. Structures < 5 microns in length do not appear to make any contribution to lung tumor risk. This analysis did not find a difference in the potency of chrysotile and amphibole toward the induction of lung tumors. However, mineralogy appears to be important in the induction of mesothelioma with chrysotile being less potent than amphibole.