Detrimental and protective bystander effects: a model approach.

This work integrates two important cellular responses to low doses, detrimental bystander effects and apoptosis-mediated protective bystander effects, into a multistage model for chromosome aberrations and in vitro neoplastic transformation: the State-Vector Model. The new models were tested on representative data sets that show supralinear or U-shaped dose responses. The original model without the new low-dose features was also tested for consistency with LNT-shaped dose responses. Reductions of in vitro neoplastic transformation frequencies below the spontaneous level have been reported after exposure of cells to low doses of low-LET radiation. In the current study, this protective effect is explained with bystander-induced apoptosis. An important data set that shows a low-dose detrimental bystander effect for chromosome aberrations was successfully fitted by additional terms within the cell initiation stage. It was found that this approach is equivalent to bystander-induced clonal expansion of initiated cells. This study is an important step toward a comprehensive model that contains all essential biological mechanisms that can influence dose-response curves at low doses.

A model for the induction of chromosome aberrations through direct and bystander mechanisms.

A state vector model (SVM) for chromosome aberrations and neoplastic transformation has been adapted to describe detrimental bystander effects. The model describes initiation (formation of translocations) and promotion (clonal expansion and loss of contact inhibition of initiated cells). Additional terms either in the initiation model or in the rate of clonal expansion of initiated cells, describe detrimental bystander effects for chromosome aberrations as reported in the scientific literature. In the present study, the SVM with bystander effects is tested on a suitable dataset. In addition to the simulation of non-linear effects, a classical dataset for neoplastic transformation in C3H 10T1/2 cells after alpha particle irradiation is used to show that the model without bystander features can also describe LNT-like dose responses. A published model for bystander induced neoplastic transformation was adapted for chromosome aberration induction and used to compare the results obtained with the different models.

Modeling lung cancer incidence in rats following exposure to radon progeny.

Lung cancer incidence in Sprague-Dawley rats was simulated by a biologically based carcinogenesis model, which is formulated mathematically in terms of a stochastic state-vector model. Doses to the sensitive target cells in the bronchial epithelium of the rat lung were calculated by a stochastic dosimetry model, considering the distinct monopodial branching structure and the crossfire of alpha particles from alveolar tissue to bronchial epithelium. Bronchial and alveolar cellular doses could reasonably be approximated by lognormal distributions, with geometric standard deviations (GSD) between 7 and 10, depending on exposure conditions. Based on a dose-exposure conversion factor of 8.5 mGy WLM(-1) and a GSD of 8, lung cancer incidences were calculated for each cumulative exposure category in the rat inhalation study, consisting of different exposure rates and exposure times. The fair agreement between theoretical predictions and experimental data over the whole exposure range emphasises the necessity to incorporate the full cellular dose distributions rather than their mean values.

Energy deposition, cellular radiation effects and lung cancer risk by radon progeny alpha particles.

Slowing down spectra, LET spectra, hit probabilities, and radiation doses were simulated for the interaction of single 218Po and 214Po alpha particles with sensitive basal and secretory cell nuclei in the bronchial epithelium of human and rat lungs for defined exposure conditions. Probabilities per unit track length for transformation, derived from in vitro experiments with C3H 10T1/2 cells, were used to estimate transformation probabilities for randon progeny alpha particles in basal and secretory cells. Different weighting schemes were assumed to relate cellular hit probabilities, doses and transformation probabilities, obtained for different cell depths and airway generations, to lung cancer risk per unit exposure. In vitro transformation and in vivo lung cancer incidence were simulated by a state-vector model which provides a stochastic formulation of dose-rate dependent cellular transitions related to formation of double strand breaks, repair, inactivation, stimulated mitosis and promotion through loss of intercellular communication.

Explanation of protective effects of low doses of gamma-radiation with a mechanistic radiobiological model.

PURPOSE: To test whether data that show protective effects of low doses against spontaneous neoplastic transformation of C3H 10T1/2 cells can be explained with a biomathematical model that includes radioprotective mechanisms. To link important features of the model to known biological processes. MATERIALS AND METHODS: The model simulates double-strand break formation in transcriptionally active and in bulk DNA, translocation of DNA segments, and the fixation of damage at mitosis; promotion is also included. The model equations were solved numerically using a stiff solver. RESULTS: The data were successfully simulated by the model: cell transformation-reducing effects of low doses of gamma-radiation delivered at low dose-rates are explained by radiation-inducible DNA repair and enzymatic scavenging. CONCLUSIONS: The model successfully simulates experimental data. The highly nonlinear features of the data point to a nonlinear dose-effect relationship at low doses and indicate that linear extrapolation from moderate (or high) to low doses and dose-rates may not be justified for in vitro studies of the cell line under consideration.

The use of a multimedia risk analysis approach in designing waste management strategies.

A pollution source may release residuals to any of several environmental media, depending on the process design and control strategies. These residuals then are subject to transfer, transport, and transformation within the interconnected compartments of the environmental system. The exposure and susceptibility of people and other receptors to pollutants are different in these various media, and so that risks imposed will vary according to the fate of the pollutants in the system. Because of interactions between compartments in the system, a single-medium approach to environmental management that mitigates problems in one environmental medium at a time independently of risk through other media may not minimize the aggregate risk a receptor receives from all pathways. Alternatively, a multimedia approach advocates focusing on the full environmental system providing pathways for exposure and selecting risk management strategies based on minimization of the aggregate and cumulative risk from all pathways and all compounds. This study combines multimedia risk analysis and an optimization framework to examine a methodology for selecting waste treatment/disposal and pollution control measures, applies the methodology to a sludge management decision problem, and considers the implications for continued use of single-medium analyses.

Significance of cell-cycle delay, multiple initiation pathways, misrepair and replication errors in a model of radiobiological effects.

PURPOSE: To advance a biomathematical model of radiocarcinogenesis by describing multiple pathways for initiation, a radiologically induced cell-cycle delay, misrepair and spontaneous DNA damages caused by replication. It was investigated whether the incorporation of these biological features would improve the fit of the model to data showing plateaus in in vitro irradiations of different cell lines and whether the fit parameters were then more biologically realistic. MATERIALS AND METHODS: A biomathematical submodel was developed based on a previous State-Vector Model that mathematically described enhanced DNA repair and radical scavenging following irradiation. RESULTS: With the two initiation pathways and cell-cycle delay, the simulations better explained the mouse data but not the rat data, and for both data sets the fit parameters were biologically more realistic than previously assumed. Inclusion of misrepair and replicational errors did not significantly affect the fit. CONCLUSIONS: A plateau in the dose-effect relationship for in vitro irradiation of different cell lines can be explained by radioprotective mechanisms. The plateau-type dose-response relationships point to a non-linear dose- effect relationship at low doses and indicate that linear extrapolation from moderate (or high) to low doses may not be justified for in vitro studies of these cell lines.

Correlated hit probability and cell transformation in an effect-specific track length model applied to in vitro alpha irradiation.

In estimating the risk from low doses of alpha particles such as those emitted by radon progeny, it is important to consider the correlation between cellular inactivation and transformation that can exist at the cellular level. A phenomenological model of radiation-induced cellular inactivation and transformation at this level is presented here which incorporates aspects of a state vector model of radiation carcinogenesis and of correlated hit probabilities for inactivation and transformation. The general form of the model assumes that both inactivation and initial initiation damage are produced through the interaction of sublesions induced by radiation passing through cell nuclei, with the production of sublesions governed by hit probabilities and a characteristic probability-per-unit track length. The inactivation and initiation events are partially correlated through the use of hit probabilities. In addition, promotional events are incorporated for the case of cellular transformation based on a previously published state vector model. The model provides good fits to available data on the relationship between inactivation, transformation and LET for doses of alpha above 0.1 Gy in the range of LETs commonly produced by radon and progeny; by "good fits" we mean here the ability to yield the correct shapes of dose-response data using parameter values that vary smoothly with LET and using inactivation parameters that are applied consistently between inactivation and transformation assays. The resulting model correctly predicts recent findings indicating an increased transformation frequency per surviving cell when a population receives a distribution of hits compared to irradiation where all cells receive the same number of hits.

Evaluation of biologically based dose-response modeling for developmental toxicity: a workshop report.

Biologically based dose-response (BBDR) modeling represents a novel approach for quantitative assessment of health risk by incorporating pharmacokinetic and pharmacodynamic characteristics of a chemical and by relating the immediate cellular responses to a cascade of aberrant biological actions that leads to detectable adverse outcomes. The quantitative relationship of each of the intervening events can be described in mathematical forms that are amenable for adjustment and extrapolation over a range of doses and across species. A team of investigators at the Reproductive Toxicology Division of the U.S. Environmental Protection Agency has explored the feasibility of BBDR modeling by examining the developmental toxicity of a known teratogen, 5-fluorouracil. A panel of researchers from academic and industrial laboratories, biomathematical modelers, and risk assessment scientists was convened in a workshop to evaluate the approaches undertaken by the EPA team and to discuss the future prospects of BBDR modeling. This report summarizes the lessons learned from one approach to BBDR modeling and comments from the panelists: while it is possible to incorporate mechanistic information into quantitative dose-response models for the assessment of health risks, the process is enormously data-intensive and costly; in addition, the confidence of the model is directly proportional to our current understanding of basic biology and can be enhanced only through the ongoing novel discoveries. More importantly, the extent of "uncertainty" (inherent with the default assumptions associated with the NOAEL or benchmark approach) reducible by BBDR modeling requires further scrutiny and comparison.

Modeling energy deposition and cellular radiation effects in human bronchial epithelium by radon progeny alpha particles.

Energy deposition and cellular radiation effects arising from the interaction of single 218Po and 214Po alpha particles with basal and secretory cell nuclei were simulated for different target cell depths in the bronchial epithelium of human airway generations 2, 4, 6, and 10. To relate the random chord lengths of alpha particle tracks through spherical cell nuclei to the resulting biological endpoints, probabilities per unit track length for different cellular radiation effects as functions of LET were derived from in vitro experiments. The radiobiological data employed in the present study were inactivation and mutation (mutant frequency at the HPRT gene) in V79 Chinese hamster cells and inactivation and transformation in C3H 10T1/2 cells. Based on computed LET spectra and relative frequencies of target cells, probabilities for transformation, mutation, and cell killing in basal and secretory cells were computed for a lifetime exposure of 20 WLM. While predicted transformation probabilities were about two orders of magnitude higher than mutation probabilities, they were still about two orders of magnitude lower than inactivation probabilities. Furthermore transformation probabilities for basal cells are generally higher than those for secretory cells, and 214Po alpha particles are primarily responsible for transformations in bronchial target cells.

Extension of a generalized state-vector model of radiation carcinogenesis to consideration of dose rate.

Mathematical models for radiation carcinogenesis typically employ transition rates that either are a function of the dose to specific cells or are purely empirical constructs unrelated to biophysical theory. These functions either ignore or do not explicitly model interactions between the fates of cells in a community. This paper extends a model of mitosis, cell transformation, promotion, and progression to cases in which interacting cellular communities are irradiated at specific dose rates. The model predicts that lower dose rates are less effective at producing cancer when irradiation is by X- or gamma rays but are generally more effective in instances of irradiation by alpha particles up to a dose rate in excess of 0.01 Gy/day. The resulting predictions are compared with existing experimental data.

Modeling the modification of the risk of radon-induced lung cancer by environmental tobacco smoke.

The presence of environmental tobacco smoke (ETS) in homes has been implicated in the causation of lung cancer. While of interest in its own right, ETS also influences the risk imposed by radon and its decay products. The interaction between radon progeny and ETS alters the exposure, intake, uptake, biokinetics, dosimetry, and radiobiology of those progeny. The present paper details model predictions of the various influences of ETS on these factors in the U.S. population and provides estimates of the resulting change in the risk from average levels of radon progeny. It is predicted that the presence of ETS produces a very small (perhaps unmeasurable) increase in the risk of radiation-induced tracheobronchial cancer in homes with initially very high particle concentrations for both active and never-smokers, but significantly lowers the risk in homes with initially lower particle concentrations for both groups when generation 4 of the lung is considered the target site. For generation 16, the presence of ETS generally increases the radon-induced risk of lung cancer, although the increase should be unmeasurable at high initial particle concentrations. The net effect of ETS on human health is suggested to be a complicated function of the initial housing conditions, the concentration of particles introduced by smoking, the target generation considered, and the smoking status of exposed populations. This situation precludes any simple statements concerning the role of ETS in governing the incidence of lung cancer in a population.

An effect-specific track-length model for radiations of intermediate to high LET.

A model for the induction of transformation, mutation, and cell killing by radiations of intermediate to high linear energy transfer (LET) is presented. The mathematical formulation presupposes a constant probability per unit path length for damaging multiple subcellular targets by radiation of a fixed LET. The coupling between effects is accounted for through an explicit calculation of the probability that any specific combination of effects occurs in a given cell. This feature avoids the false assumption that cell killing and mutation (or transformation) are independent events. The resulting model then is applied to data on the in vitro survival, mutation, and transformation of cells by radiations of varying LET. A summary of estimated parameter values is provided and calculations of the effect of cellular flattening on transformation are presented.

Cancer fatalities from waterborne radon (Rn-222).

A model of the biokinetics of radon in the human body following ingestion is developed from existing data. Calculations of the probability of cancer fatality from use of radon-laden water in the home then are presented. The pathways of emanation and ingestion are examined and shown to lead to roughly equal risks. The probability of fatal cancer resulting from lifetime use of water at a radon concentration of 1 pCi/L is shown to be 1 X 10(-6), with a reasonable range between 2 X 10(-7) and 5 X 10(-6). The allowed concentration consistent with an excess risk of 10(-4) then is approximately 100 pCi/L, which is exceeded in a significant fraction of U.S. water supplies. The lifetime number of premature deaths due to waterborne radon in the U.S. is estimated to lie between 5000 and 125,000, with a best estimate of 25,000.

A generalized state-vector model for radiation-induced cellular transformation.

A mathematical model is developed, detailing the manner in which radiation brings about the transformation of cells to a state of uncontrolled growth. The model is based on the concepts of initiation and promotion, with the irradiation acting both to damage intracellular structures and to change the state of cells surrounding a damaged (initiated) cell. The complete model requires that the radiation produce two forms of damage within a cell, with at least one of the forms requiring an interaction which is a function of time since irradiation. Some form of contact inhibition must be removed, with this step being a function of the probability that a cell in an initiated state will be surrounded by n dead cells. The cell then must divide, with the probability of moving the cell to the final transformed state being a function of the number of cellular divisions. Prior to irradiation, it is assumed that cells may be characterized by an initial state vector describing the probability that any given cell is in one of the states specified by the model. The resulting model then is used to explain data concerning in vitro irradiation of cells by acute doses of X-rays, alpha particles and neutrons. Limited tests of the theory under conditions of fractionated irradiation are also provided. A controlling factor in such studies is the number of cells already in intermediate states prior to the irradiation.

The biokinetics and dosimetry of radon-222 in the human body following ingestion of groundwater.

This paper presents a general model for the biokinetics of Rn-222 in the adult human body following ingestion of the radon in water. Such a model is needed for the calculation of doses which would result from the ingestion of radon, a natural component of drinking water supplies. Information on the movement and concentration of xenon in the body was obtained from a separate study conducted at the Massachusetts General Hospital. This information was used to develop a model of radon kinetics in the body and estimates were obtained of the rate constants associated with transfer between the various body compartments. The model was then used to develop estimates of the dose equivalent delivered to each tissue or organ of the body following ingestion of 1 Bq of radon in water. From the reported results, it appears that the stomach receives a much larger dose equivalent than other organs and tissues, followed in order by the other segments of the gastro-intestinal or Gl tract, the liver, the lungs and the general body water compartment. A comparison is made between these doses and the doses delivered as a result of exposure to airborne radon.

Radiation doses and cause-specific mortality among workers at a nuclear materials fabrication plant.

A historical cohort mortality study was conducted among 6,781 white male employees from a nuclear weapons materials fabrication plant for the years 1947-1979. Exposures of greatest concern are alpha and gamma radiation emanating primarily from insoluble uranium compounds. Among monitored workers, the mean cumulative alpha radiation dose to the lung was 8.21 rem, and the mean cumulative external whole body penetrating dose from gamma radiation was 0.96 rem. Relative to US white males, the cohort experienced mortality deficits from all causes combined, cardiovascular diseases, and from most site-specific cancers. Mortality excesses of lung and brain and central nervous system cancers were seen from comparisons with national and state rates. Dose-response trends were detected for lung cancer mortality with respect to cumulative alpha and gamma radiation, with the most pronounced trend occurring for gamma radiation among workers who received greater than or equal to 5 rem of alpha radiation. These trends diminished in magnitude when a 10-year latency assumption was applied. Under a zero-year latency assumption, the rate ratio for lung cancer mortality associated with joint exposure of greater than or equal to 5 versus less than 1 rem of both types of radiation is 4.60 (95% confidence limits (CL) 0.91, 23.35), while the corresponding result, assuming a 10-year latency, is 3.05 (95% CL 0.37, 24.83). While these rate ratios, which are based on three and one death, respectively, lack statistical precision, the observed dose-response trends indicate potential carcinogenic effects to the lung of relatively low-dose radiation. There are no dose-response trends for mortality from brain and central nervous system cancers.

Predicting the occurrence of radon-222 in groundwater supplies.

The intent of this study was to develop an understanding of some of the factors that affect the concentration ol radon-222 ((222)Rn) in drinking water supplies derived from groundwater, with specific application to North Carolina. Data for this investigation were collected on a sample of 96 North Carolina public water supply wells. Water samples were collected and analyzed for(222)Rn content. Data on site geology and well characteristics (discharge, specific capacity, depth, and casing length) were obtained from existing sources. From a statistical examination of the data collected in this study, we conclude that there is a distinct and statistically significant difference in the mean(222)Rn concentrations of groundwater associated with different types of rocks. The data, however, also indicate that there is a great degree of variability in the(222)Rn concentrations of samples drawn from any giver rock type. The situation is made slightly better by introducing a second variable given as the geologic region of a water supply. A fairly surprising finding of this study is the relative insignificance of discharge, specific capacity, depth, and casing length of wells as predictors of(222)Rn concentration. The present study indicates that use of these variables as predictors does not significantly improve the likelihood of locating water supplies with elevatec(222)Rn concentrations.

A Bayesian analysis or scientific judgment of uncertainties in estimating risk due to 222Rn in U.S. public drinking water supplies.

The elements which contribute to the range of values or uncertainties for the lifetime risk and dose equivalent due to 222Rn in U.S. public drinking water supplies are estimated and discussed here. From imperfect scientific knowledge, reasonable upper and lower bounds are placed on these estimates through the use of a semiquantitative Bayesian approach to uncertainty analysis. The factors considered are: occurrence of 222Rn in drinking water, indoor air 222Rn concentrations as a function of drinking water concentration, equilibrium state of the progeny, fraction of daughter products attached to aerosol particles, anatomical and dosimetric variables, epidemiological studies and choice of latency period, plateau period and effects of age. For Rn in U.S. public drinking water supplies, it is estimated that the best estimate for the lifetime lung cancer risk factor is 5 X 10(-9) excess cases of lung cancer per becquerel of Rn per m3 of water (2 X 10(-7) excess cases of lung cancer per picocurie of Rn per liter of water), with an estimated range between 2 X 10(-9) and 2 X 10(-8) excess cases per becquerel of Rn per m3 of water (5 X 10(-8) and 7 X 10(-7) excess cases per picocurie of Rn per liter). The best estimate of the lifetime population risk due to 222Rn in U.S. public drinking water supplies is estimated to be 6,000 excess lung cancers, with a reasonable range of 1,000 to 30,000.