Lung tumour risk in radon-exposed rats from different experiments: comparative analysis with biologically based models

Data sets of radon-exposed male rats from Wistar and Sprague-Dawley strains have been investigated with two different versions of the two-step clonal expansion (TSCE) model of carcinogenesis. These so-called initiation-promotion (IP) and initiation-transformation (IT) models are named after the cell-based processes that are assumed to be induced by radiation. The analysis was done with all malignant lung tumours taken to be incidental and with fatal tumours alone. For all tumours treated as incidental, both models could explain the tumour incidence data equally well. Owing to its better fit, only the IP model was applied in the analysis of fatal tumours that carry additional information on the time when they cause death. A statistical test rejected the hypothesis that a joint cohort of Wistar and Sprague-Dawley rats can be described with the same set of model parameters. Thus, the risk analysis has been carried out for the Wistar rats and the Sprague-Dawley rats separately and has been restricted to fatal tumours alone because of their similar effect in humans. Using a refined technique of age-adjustment, the lifetime excess absolute risk has been standardised with the survival function from competing risks in the control population. The age-adjusted excess risks for both strains of rats were of similar size, for animals with first exposure later in life they decreased markedly. For high cumulative exposure the excess risk increased with longer exposure duration, for low cumulative exposure it showed the opposite trend. In addition, high cumulative exposure exerted lethal effects other than lung cancer on the rats.     

Development of a physiologically based toxicokinetic model for butadiene and four major metabolites in humans: global sensitivity analysis for experimental design issues

1,3-Butadiene (BD) is metabolized in humans and rodents to mutagenic and carcinogenic species. Our previous work has focused on developing a physiologically based toxicokinetic (PBTK) model for BD to estimate its metabolic rate to 1,2-epoxy-3-butene (EB), using exhaled breath BD concentrations in human volunteers exposed by inhalation. In this paper, we extend our BD model to describe the kinetics of its four major metabolites EB, 1,2:3,4-diepoxybutane (DEB), 3-butene-1,2-diol (BDD), and 3,4-epoxy-1,2-butanediol (EBD), and to test whether the extended model and experimental data (to be collected for BD and metabolites in humans) are together adequate to estimate the metabolic rate constants of each of the above chemicals. Global sensitivity analyses (GSA) were conducted to evaluate the relative importance of the model parameters on model outputs during the 20min of exposure and the 40min after exposure ended. All model parameters were studied together with various potentially measurable model outputs: concentrations of BD and EB in exhaled air, concentrations of BD and all metabolites in venous blood, and cumulated amounts of urinary metabolites excreted within 24h. Our results show that pulmonary absorption of BD and subsequent distribution and metabolism in the well-perfused tissues compartment are the critical processes in the toxicokinetics of BD and metabolites. In particular, three parameters influence numerous outputs: the blood:air partition coefficient for BD, the metabolic rate of BD to EB, and the volume of the well-perfused tissues. Other influential parameters include other metabolic rates, some partition coefficients, and parameters driving the gas exchanges (in particular, for BD outputs). GSA shows that the impact of the metabolic rate of BD to EB on the BD concentrations in exhaled air is greatly increased if a few of the model's important parameters (such as the blood:air partition coefficient for BD) are measured experimentally. GSA also shows that all the transformation pathways described in the PBTK model may not be estimable if only data on the studied outputs are collected, and that data on a specific output for a chemical may not inform all the transformations involving that chemical.     

Process of building biologically based dose-response models for developmental defects.

The problem of developing biologically-based dose-response models is addressed for predicting the prevalence of birth defects at low doses of toxic chemicals administered during pregnancy. To illustrate the process of incorporating biological information, a model is postulated to predict the prevalence of cleft palate for a chemical that reduces embryonic/fetal growth, which results in inadequate palatal cells for closure. Experimental bioassay data examining the prevalence of cleft palate in mice exposed to the herbicide 2,4,5-T are used to illustrate the process. With the limited data available, it is necessary to assume a model for cell growth and the relationship between the cell growth rate parameter and dose of 2,4,5-T. Also, a relationship between cleft palate prevalence and growth is assumed and then checked with experimental data. The purpose of the paper is not to provide a universal biologically based dose-response model for cleft palate, but rather to demonstrate the extent, and type of information and data required. It remains to be seen if the form of the model is appropriate for chemicals that primarily produce embryo/fetal malformations or death via reduced or delayed cellular growth.     

A biologically based model for liver cancer risk in the Swedish thorotrast patients

Data on liver tumors among 416 Swedish patients who were exposed to Thorotrast between 1930 and 1950 were analyzed with the biologically based two-step clonal expansion (TSCE) model. For background data, the Swedish Cancer Register for the follow-up period 1958 to 1997 was used. Effects of radiation on the initiating mutation and on the clonal expansion rate explained the observed patterns well. The TSCE model permits the deduction of several kinetic parameters of the postulated tumorigenesis process. Dose rates of 5 mGy/year double the spontaneous initiation rate. The clonal expansion rate is doubled by 80 mGy/year, and for females it reaches a plateau at dose rates beyond 240 mGy/year. For males the plateau is not significant. The magnitude of the estimated promoting effect of radiation can be explained with a moderate increase in the cell replacement probability for the intermediate cells in the liver, which is strikingly similar to the situation in lung tumorigenesis.     

Use of the individual data of the a-bomb survivors for biologically based cancer models

All recent analyses of the data on solid cancer incidence of the atomic bomb survivors are corrected for migration and random dose errors. In the usual treatment with grouped data and regression calibration, the calibration of doses depends on the used dose response. For solid cancers, it usually is linear. Here, an individual likelihood is presented which works without further adjustment for all dose responses. When the same assumptions are made as in the usual Poisson regression, equivalent results are obtained. But, the individual likelihood has the potential to use more detailed models for dose errors and to estimate non-linear dose responses without recalibration. As an example for the potential of the individual data set for the analysis of risk at low doses, signals for a saturating bystander effect are investigated.     

Well-posedness of physiologically structured population models for Daphnia magna

In this paper we heuristically discuss the well-posedness of three variants of the Kooijman/Metz model. Shortcomings concerning the uniqueness and continuous dependence on data of the solutions to one of the variants are traced back to an inconsistency in the biological concept of energy allocation in this model version. The conceptional consequences are discussed and an open question concerning energy allocation is pin-pointed.     

The role of predation in plankton models

Models of carbon and nitrogen cycles in the ocean are a majortool in elucidating short-and long-term patterns of chemicalfluxes. Variability in space and time are usually attributedto changes in ocean physics at different scales. This paperstresses the significance of the upper (predatory) closure inthese simple nutrient-plant-herbivore models. The mathematicalform used to close the system and the values given to the parametershave very marked effects on the overall response. In particularthe major differences between North Atlantic and Pacific patternsmay depend on this aspect as much as on the physical cycles.It is shown that the selection of different closure forms infive recent modelling studies corresponds to differences inthe nutrient dynamics and plankton cycles. Thus, in general,the character of the results from these models will depend onboth the form of the mortality closure and the parameter valuesused. Our ignorance in both areas is considerable.     

Avenues for increasing salt tolerance of crops,and the role of physiologically based selection traits

Increased salt tolerance is needed for crops grown in areas at risk of salinisation. This requires new genetic sources of salt tolerance, and more efficient techniques for identifying salt-tolerant germplasm, so that new genes for tolerance can be introduced into crop cultivars. Screening a large number of genotypes for salt tolerance is not easy. Salt tolerance is achieved through the control of salt movement into and through the plant, and salt-specific effects on growth are seen only after long periods of time. Early effects on growth and metabolism are likely due to osmotic effects of the salt, that is to the salt in the soil solution. To avoid the necessity of growing plants for long periods of time to measure biomass or yield, practical selection techniques can be based on physiological traits. We illustrate this with current work on durum wheat, on selection for the trait of sodium exclusion. We have explored a wide range of genetic diversity, identified a new source of sodium exclusion, confirmed that the trait has a high heritability, checked for possible penalties associated with the trait, and are currently developing molecular markers. This illustrates the potential for marker-assisted selection based on sound physiological principles in producing salt-tolerant crop cultivars.     

The application of mass and energy conservation laws in physiologically structured population models of heterotrophic organisms

Rules for energy uptake, and subsequent utilization, form the basis of population dynamics and, therefore, explain the dynamics of the ecosystem structure in terms of changes in standing crops and size distributions of individuals. Mass fluxes are concomitant with energy flows and delineate functional aspects of ecosystems by defining the roles of individuals and populations. The assumption of homeostasis of body components, and an assumption about the general structure of energy budgets, imply that mass fluxes can be written as weighted sums of three organizing energy fluxes with the weight coefficients determined by the conservation law of mass. These energy fluxes are assimilation, maintenance and growth, and provide a theoretical underpinning of the widely applied empirical method of indirect calorimetry, which relates dissipating heat linearly to three mass fluxes: carbon dioxide production, oxygen consumption and N-waste production. A generic approach to the stoichiometry of population energetics from the perspective of the individual organism is proposed and illustrated for heterotrophic organisms. This approach indicates that mass transformations can be identified by accounting for maintenance requirements and overhead costs for the various metabolic processes at the population level. The theoretical background for coupling the dynamics of the structure of communities to nutrient cycles, including the water balance, as well as explicit expressions for the dissipating heat at the population level are obtained based on the conservation law of energy. Specifications of the general theory employ the Dynamic Energy Budget model for individuals. Copyright 1999 Academic Press.     

Genetic background and <Superscript>227</Superscript>Thorium as risk factors in biologically based models for induction of bone cancer in mice

We explore the potential for the biologically based two-stage clonal expansion model to make statements about the influence of genetic factors on the steps in the model. We find evidence that the different susceptibility of BALB/C and CBA/Ca mice to bone cancer after ²²⁷Thorium injection may be mostly due to different promotional responses to radiation. In BALB/C × CBA/Ca back-crossed mice, we analyzed the specific contribution of two individual loci in the carcinogenic process. This analysis suggests that the two high- or low-risk alleles are acting on promotion or on the background parameters, but not on radiation-induced initiation. Taken together with the comparison of CBA/Ca and BALB/C mice, this hints at the possibility that the two loci are candidates for modifying radiation-induced promotion.     

Emerging role of myeloperoxidase and oxidant stress markers in cardiovascular risk assessment

PURPOSE OF REVIEW: Myeloperoxidase, an abundant leukocyte protein that generates reactive oxidant species, is present and catalytically active within atherosclerotic lesions. Numerous lines of evidence suggest mechanistic links between myeloperoxidase, inflammation and both acute and chronic manifestations of cardiovascular disease. RECENT FINDINGS: Myeloperoxidase generates reactive oxidant species as part of its function in innate host defense mechanisms. The reactive species formed, however, may also damage normal tissues, contributing to inflammatory injury. Recent studies suggest that MPO-generated oxidants participate in multiple processes relevant to cardiovascular disease development and outcomes, including induction of foam cell formation, endothelial dysfunction, development of vulnerable plaque, and ventricular remodeling following acute myocardial infarction. Of note, measurements of myeloperoxidase mass and activity may be useful in cardiac risk stratification, both for chronic disease assessment, as well as in identification of patients at risk in the acute setting. SUMMARY: The inflammatory protein myeloperoxidase is present, active and mechanistically poised to participate in the initiation and progression of cardiovascular disease. The many links between myeloperoxidase, oxidation and cardiovascular disease suggest this leukocyte protein may have clinical utility in risk stratification for cardiovascular disease status and outcomes.     

Developments in microbiological risk assessment models for drinking water—a short review

Microbiological risk assessment (MRA) is the emerging method to predict the risks of infection from waterborne pathogens (e.g. rotavirus and Cryptosporidium parvum ) in the drinking water supply. The objectives of this paper are to review the appropriateness of current models, with emphasis on pathogen exposures through drinking water, and to consider the information necessary to further their development. Calculating pathogen exposures in MRA is currently limited by the fact that pathogen density data for drinking water supplies are only available for very large volume samples—much larger than imbibed daily by any consumer. To develop MRA, information is needed on how pathogens are dispersed within those large volumes at the resolution of volumes typically consumed daily by individuals. Available evidence suggests that micro-organisms, including pathogens, are clustered to some degree, even within small volumes, exposing some drinking water consumers to much higher doses than others. By assuming pathogens are randomly dispersed, current models overestimate the risk from the more infectious agents (e.g. rotaviruses) but underestimate the risk from less infectious pathogens (e.g. C. parvum ). Approaches to modelling pathogen densities in drinking water from source water data and treatment removal efficiencies require additional information on the degree to which treatment processes (e.g. filtration and coagulation) increase pathogen clustering. The missing information could be obtained from large-scale pilot plant studies.     

Novel biologically based therapeutic strategies in myeloma

Multiple myeloma remains incurable despite advances in conventional chemotherapy and wider applicability of high dose chemotherapy with single and/or tandem autologous peripheral blood stem cell transplantation. Although a complete remission rate of 41% and an event-free survival of 43 months have been reported after tandem transplantation, it is highly unlikely that further improvements in the outcome of multiple myeloma will be achieved by escalating cytotoxic chemotherapy alone. Novel biologically based therapies are therefore urgently required. Targeted therapeutic approaches based on: identification of genetic abnormalities in malignant plasma cells; interrupting growth of myeloma cells; triggering apoptotic signaling cascades in tumor cells; modulating growth and survival of multiple myeloma cells in the bone marrow microenvironment, i.e. angiogenesis and cytokine networks; enhancing allogeneic and autologous antimyeloma immunity; and characterizing newer myeloma antigens for serotherapy are under development. These therapies offer great promise, used alone/or in combination with conventional treatment approaches, to improve the outcome in this disease in newly diagnosed/refractory or relapsed patients with multiple myeloma.     

Future directions in butadiene risk assessment and the role of cross-species internal dosimetry

The 2005 International Symposium on the evaluation of butadiene and chloroprene health risks provided the opportunity to consider the past, present and future state of research issues for 1,3-butadiene. Considerable advancements have been made in our knowledge of exposure, metabolism, biomarkers of exposure and effect, and epidemiology. Despite this, uncertainties remain which will impact the human health risk assessment for current worker and environmental exposures. This paper reviews key aspects of recent studies and the role that biomarkers of internal dosimetry can play in addressing low to high exposure, gender, and cross-species differences in butadiene toxicity and metabolism. Considerable information is now available on the detection and quantification of protein adducts formed from the mono-, di- and dihydroxy-epoxide metabolites of butadiene. The diepoxide metabolite appears to play a key role in mutagenesis. Species differences in production of this critical metabolite are reflected by the diepoxybutane-specific hemoglobin adduct, pry-Val. To date, the pry-Val adduct has not been quantifiable in human blood samples from workers with cumulative occupational exposures up to 6.3 ppm-weeks; whereas, the pry-Val was quantifiable in the blood of mice and rats with similar cumulative exposures. Levels in mice were much higher than in rats. Further improvements in analytical sensitivity for the pyr-Val adduct are on the horizon. Epidemiology studies are also described and ongoing efforts promise to help bridge our understanding of past and future risks.     

Scientific principles for ecologically based risk assessment of transgenic organisms

It is critical to base scientific risk assessment of genetically engineered organisms (GEOs) on appropriate scientific concepts. A variety of 'generic safety' models has now largely been recognized to have been based on outdated scientific thinking. One broad safety argument that is still used is that genetic engineering categorically is nothing but an extension of selective breeding. It is explained here, though, that the mechanisms and potentials of the two can be profoundly different. This does not mean that every GEO is ecologically dangerous; but some types of GEOs may be considerably more risky than what could be produced with selective breeding, especially when an ecologically competent host is supplemented with novel features that may increase its competitiveness. In addition, genetic 'side effects' raise food-safety issues; and the possibility that they may sometimes increase ecological competitiveness cannot be ruled out, though this would be quite rare. Field plots have a proper use: to gather particular data that could be used in analysing the risks of commercial releases. But it is not scientific to call a small, confined, field population, isolated from potential competitors, a 'test or release' and then conclude that because 'nothing happened' the GEO will be safe when commercialized, or indeed that all GEOs will be safe.