Dynamic load response of human dura mater at different velocities.

Despite of its assumed role to mitigate brain tissue response under dynamic loading conditions, the human dura mater is frequently neglected in computational and physical human head models. A reason for this is the lack of load-deformation data when the dura mater is loaded dynamically. To date, the biomechanical characterization of the human dura mater predominantly involved quasi-static testing setups. This study aimed to investigate the strain rate-dependent mechanical properties of the human dura mater comparing three different velocities of 0.3, 0.5 and 0.7 m/s. Samples were chosen in a perpendicular orientation to the visible main fiber direction on the samples' surface, which was mostly neglected in previous studies. The elastic modulus of dura mater significantly increased at higher velocities (5.16 [3.38; 7.27] MPa at 0.3 m/s versus 44.38 [35.30; 74.94] MPa at 0.7 m/s). Both the stretch at yield point λf (1.148 [1.137; 1.188] for 0.3 m/s, 1.062 [1.054; 1.066] for 0.5 m/s and 1.015 [1.012; 1.021] for 0.7 m/s) and stress at yield point σf of dura mater (519.14 [366.74; 707.99] kPa for 0.3 m/s versus 300.52 [245.31; 354.89] kPa at 0.7 m/s) significantly decreased with increasing velocities. Conclusively, increasing the load application velocity increases stiffness and decreases tensile strength as well as straining potential of human dura mater between 0.3 and 0.7 m/s. The elastic modulus of human dura mater should be adapted to the respective velocities in computational head impact simulations.

The relationship between the pH value of a hydration solution and the biomechanical properties of Crosado-embalmed human iliotibial bands.

Determining the biomechanical properties of human tissues commonly involves the immersion or spraying of the tissues to maintain them in a hydrated state. However, the influence of the pH value of these solutions on the biomechanical properties of the tissues is not well understood. This study investigated the effects of the pH value on the biomechanical properties of the collagen-rich human iliotibial band (ITB). A total of 124 samples were allocated to polyethylene glycol (PEG) solutions of pH values between 3 and 13 for 24 h, which is a frequently used immersion time prior to biomechanical tests. After this, the samples were biomechanically tested in a uniaxial tensile testing setup using an established testing routine. Similarly, 69 samples were allocated to pH groups of 6, 7 and 8 and biomechanically tested after 1, 2 and 3 weeks. The cross-sectional area of all samples was determined after immersion into the PEG solutions for the specified time frames. In the 24-h experiment, the elastic modulus (pH 12: p ≤ 0.045; pH 13: p ≤ 0.020) and the ultimate tensile strength (pH 12: p ≤ 0.031; pH 13: p ≤ 0.026) of the pH groups 12 and 13 were significantly lower and their cross-sectional areas were higher (pH 12: p ≤ 0.005; pH 13: p ≤ 0.003) compared to several groups of acidic to alkaline pH values. There was no difference in the maximum forces between the different groups within a 24-h immersion time (p > 0.999). In the 3-week-test, a decrease of the ultimate tensile strength was noted between the 24-h and 3 week values for the pH groups 7 (p = 0.034) and 8 (p = 0.029). It is concluded that pH-dependent tissue swelling influences the cross-sectional area-dependent biomechanical properties of the human ITB. Therefore, the pH value of storage and hydration solutions for the preparation of biomechanical tests should be recorded. From a biomechanical perspective, the collagen stability of the human ITB is largely unaltered in PEG solutions with pH values between 3 and 13 over 24 h.

On the correlations of biomechanical properties of super-imposed temporal tissue layers and their age-, sex-, side- and post-mortem interval dependence.

Obtaining biomechanical properties of biological tissues for simulation purposes or graft developments is time and resource consuming. The number of samples required for biomechanical tests could be reduced if the load-deformation properties of a given tissue layer could be estimated from adjacent layers or if the biomechanical parameters were unaffected by age, bodyside, sex or post-mortem interval. This study investigates for the first time potential correlations of multiple super-imposed tissue layers using the temporal region of the human head as an area of broad interest in biomechanical modelling. Spearman correlations between biomechanical properties of the scalp, muscle fascia, muscle, bone and dura mater from up to 83 chemically unfixed cadavers were investigated. The association with age, sex and post-mortem interval was assessed. The results revealed sporadic correlations between the corresponding layers, such as the maximum force (r = 0.43) and ultimate tensile strength (r = 0.33) between scalp and muscle. Side- and age-dependence of the biomechanical properties were different between the tissue types. Strain at maximum force of fascia (r = -0.37) and elastic modulus of temporal muscle (r = 0.26) weakly correlated with post-mortem interval. Only strain at maximum force of scalp differed significantly between sexes. Uniaxial biomechanical properties of individual head tissue layers can thus not be estimated solely based on adjacent layers. Therefore, correlations between the tissues' biomechanical properties, anthropometric data and post-mortem interval need to be established independently for each layer. Sex seems not to be a relevant influencing factor for the passive tissue mechanics of the here investigated temporal head tissue layers.

Biomechanics of vascular areas of the human cranial dura mater.

Accurate biomechanical properties of the human cranial dura mater are paramount for computational head models, artificial graft developments and biomechanical basic research. Yet, it is unclear whether areas of the dura containing meningeal vessels biomechanically differ from avascular areas. Here, 244 dura mater samples with or without vessels from 32 cadavers were tested in a quasi-static uniaxial tensile testing setup. The thicknesses of the meningeal and periosteal dura in vascular and avascular areas were histologically investigated in 36 samples using van Gieson staining. The elastic modulus of 112 MPa from dura samples containing vessels running transversely was significantly lower than samples with vessels running longitudinally (151 MPa; p < 0.001). The ultimate tensile strength of dura samples with transversely running vessels (11.1 MPa) was significantly lower in comparison to both avascular samples (14.9 MPa; p < 0.001) and samples with a longitudinally running vessel (15.0 MPa; p < 0.001). The maximum force of dura samples with longitudinally running vessels was 37 N (p < 0.001), this was significantly higher compared to the other groups which were 23 N (p < 0.001). The meningeal and periosteal dura layer thicknesses were not statistically different in avascular areas (p > 0.222). However, around the vessels, the meningeal dura layer was significantly thicker compared to the periosteal layer (p ≤ 0.019). The sum of the meningeal and periosteal layers was similar between vascular and avascular areas (p ≥ 0.071). Vascular areas of the human cranial dura mater withstand the same forces as avascular areas when being stretched. When stretched along the vessel, the dura-vessel composite can withstand even higher tensile forces compared to avascular areas. Vascular areas of the cranial dura mater seem to be similar when compared to avascular areas making their separate simulation in computational models non-essential.

Changes in net ecosystem exchange over Europe during the 2018 drought based on atmospheric observations.

The 2018 drought was one of the worst European droughts of the twenty-first century in terms of its severity, extent and duration. The effects of the drought could be seen in a reduction in harvest yields in parts of Europe, as well as an unprecedented browning of vegetation in summer. Here, we quantify the effect of the drought on net ecosystem exchange (NEE) using five independent regional atmospheric inversion frameworks. Using a network of atmospheric CO2 mole fraction observations, we estimate NEE with at least monthly and 0.5° × 0.5° resolution for 2009-2018. We find that the annual NEE in 2018 was likely more positive (less CO2 uptake) in the temperate region of Europe by 0.09 ± 0.06 Pg C yr-1 (mean ± s.d.) compared to the mean of the last 10 years of -0.08 ± 0.17 Pg C yr-1, making the region close to carbon neutral in 2018. Similarly, we find a positive annual NEE anomaly for the northern region of Europe of 0.02 ± 0.02 Pg C yr-1 compared the 10-year mean of -0.04 ± 0.05 Pg C yr-1. In both regions, this was largely owing to a reduction in the summer CO2 uptake. The positive NEE anomalies coincided spatially and temporally with negative anomalies in soil water. These anomalies were exceptional for the 10-year period of our study. This article is part of the theme issue 'Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale'.

Passive load-deformation properties of human temporal muscle.

The passive load-deformation properties of the human temporal muscle applicable to computer simulations of the human head or the comparison of the temporal muscle to other graft materials are unexplored to date and it is unclear, if these properties depend on age, sex, post-mortem interval or body side. Eighty-eight fresh temporal muscle samples from 69 human cadavers (age range 4 months - 94 years) were investigated in a quasi-static tensile setup. For comparative reasons, 20 age-matched human temporal muscle fascia and scalp samples were tested in the same manner as the temporal muscle. Human temporal muscle showed an elastic modulus of 1.58 ± 0.64 MPa, an ultimate tensile strength of 0.26 ± 0.11 MPa and a strain at maximum force of 26.21 ± 12.48%. These parameters were independent of sex (p > 0.88), side (p > 0.92) and post-mortem interval (p > 0.09). All passive load-deformation parameters of the human temporal muscle differed from temporal muscle fascia and scalp except for the strain at maximum force of the temporal muscle and scalp. Significantly different load-deformation properties of the human temporal muscle from temporal muscle fascia and scalp indicate the need for a separate simulation of these soft tissue layers in computational head models to reflect lifelike conditions. Contrary to other tissues such as scalp or temporal muscle fascia the biomechanical temporal muscle properties in head models may not require adjustments for sex, side and age based on the here-presented findings.

Mechanical properties of native and acellular temporal muscle fascia for surgical reconstruction and computational modelling purposes.

The temporal muscle fascia (TMF) is a widely used graft material and of interest for computational simulations of the temporomandibular joint as well as computational and physical human head models in general. However, reliable biomechanical properties of the TMF are lacking to date. This study provides tensile data of 52 TMFs at an age range of 18 to 94 years. It further investigates, if acellular fascia scaffolds differ from native counterparts in their biomechanical behaviour. Native TMF has a median elastic modulus of 26.2 MPa (acellular: 24.5 MPa), an ultimate tensile strength of 2.9 MPa (acellular: 2.1 MPa), a maximum force of 12.6 N (acellular: 9.9 N) and a strain at failure of 14.1% (acellular: 14.8%). No significant difference was found regarding the properties of native and acellular samples. Elastic modulus and the ultimate tensile strength increased with age but only in the acellular group (p < 0.01). Decorin and fibronectin seemed to be washed out by the acellularization procedure. The absence of cells in acellular TMF samples is not of biomechanical relevance compared to the native state. Acellular TMF is a biomechanically promising scaffold material for graft purposes, which can be retrieved easily due to its superficial location.

Tensile properties of the human iliotibial tract depend on height and weight.

BACKGROUND AND AIMS: The human iliotibial tract (IT) is increasingly used in different types of musculoskeletal models. Previous findings indicate age-dependent changes of the human IT tensile properties, these lack confirmation to date. The relationship of the human IT and anthropometrical parameters, such as body height and weight has not been investigated before. MATERIALS AND METHODS: 33 fresh human IT samples (age range 4 months to 93 years) were uniaxially tested using digital imaging correlation and the latest advances in 3D-printing to standardize biomechanical soft tissues testing. RESULTS: The tensile parameters of the human IT are not age-dependent, except for the maximum strain in males. Height significantly correlated to elastic modulus, tensile strength and maximum strain of the human IT in males. Females just showed a significant correlation between maximum strain and weight, which was contrary to the findings in males. DISCUSSION AND CONCLUSION: Age-dependency of human IT tensile parameters could not be confirmed in the larger sample size investigated in this study. Due to the strong correlation with the tensile IT parameters in males, we suggest that height should be integrated when the IT is used in simulations, such as finite element analyses of the hip and knee.

EDC IMPACT: Reduced sperm counts in rats exposed to human relevant mixtures of endocrine disrupters.

Human semen quality is declining in many parts of the world, but the causes are ill defined. In rodents, impaired sperm production can be seen with early life exposure to certain endocrine-disrupting chemicals, but the effects of combined exposures are not properly investigated. In this study, we examined the effects of early exposure to the painkiller paracetamol and mixtures of human relevant endocrine-disrupting chemicals in rats. One mixture contained four estrogenic compounds; another contained eight anti-androgenic environmental chemicals and a third mixture contained estrogens, anti-androgens and paracetamol. All exposures were administered by oral gavage to time-mated Wistar dams rats (n = 16-20) throughout gestation and lactation. In the postnatal period, testicular histology was affected by the total mixture, and at the end of weaning, male testis weights were significantly increased by paracetamol and the high doses of the total and the anti-androgenic mixture, compared to controls. In all dose groups, epididymal sperm counts were reduced several months after end of exposure, i.e. at 10 months of age. Interestingly, the same pattern of effects was seen for paracetamol as for mixtures with diverse modes of action. Reduced sperm count was seen at a dose level reflecting human therapeutic exposure to paracetamol. Environmental chemical mixtures affected sperm count at the lowest mixture dose indicating an insufficient margin of safety for the most exposed humans. This causes concern for exposure of pregnant women to paracetamol as well as environmental endocrine disrupters.

Drug development against sleeping sickness: old wine in new bottles?

Atoxyl, the first medicinal drug against human African trypanosomiasis (HAT), also known as sleeping sickness, was applied more than 100 years ago. Ever since, the search for more effective, more specific and less toxic drugs continued, leading to a set of compounds currently in use against this devastating disease. Unfortunately, none of these medicines fulfill modern pharmaceutical requirements and may be considered as therapeutic ultima ratio due to the many, often severe side effects. Starting with a historic overview on drug development against HAT, we present a selection of trypanosome specific pathways and enzymes considered as highly potent druggable targets. In addition, we describe cellular mechanisms the parasite uses for differentiation and cell density regulation and present our considerations how interference with these steps, elementary for life cycle progression and infection, may lead to new aspects of drug development. Finally we refer to our recent work about CNS infection that offers novel insights in how trypanosomes hide in an immune privileged area to establish a chronic state of the disease, thereby considering new ways for drug application. Depressingly, HAT specific drug development has failed over the last 30 years to produce better suited medicine. However, unraveling of parasite-specific pathways and cellular behavior together with the ability to produce high resolution structures of essential parasite proteins by X-ray crystallography, leads us to the optimistic view that development of an ultimate drug to eradicate sleeping sickness from the globe might just be around the corner.

Anti-androgens act jointly in suppressing spiggin concentrations in androgen-primed female three-spined sticklebacks - prediction of combined effects by concentration addition.

Increasing attention is being directed at the role played by anti-androgenic chemicals in endocrine disruption of wildlife within the aquatic environment. The co-occurrence of multiple contaminants with anti-androgenic activity highlights a need for the predictive assessment of combined effects, but information about anti-androgen mixture effects on wildlife is lacking. This study evaluated the suitability of the androgenised female stickleback screen (AFSS), in which inhibition of androgen-induced spiggin production provides a quantitative assessment of anti-androgenic activity, for predicting the effect of a four component mixture of anti-androgens. The anti-androgenic activity of four known anti-androgens (vinclozolin, fenitrothion, flutamide, linuron) was evaluated from individual concentration-response data and used to design a mixture containing each chemical at equipotent concentrations. Across a 100-fold concentration range, a concentration addition approach was used to predict the response of fish to the mixture. Two studies were conducted independently at each of two laboratories. By using a novel method to adjust for differences between nominal and measured concentrations, good agreement was obtained between the actual outcome of the mixture exposure and the predicted outcome. This demonstrated for the first time that androgen receptor antagonists act in concert in an additive fashion in fish and that existing mixture methodology is effective in predicting the outcome, based on concentration-response data for individual chemicals. The sensitivity range of the AFSS assay lies within the range of anti-androgenicity reported in rivers across many locations internationally. The approach taken in our study lays the foundations for understanding how androgen receptor antagonists work together in fish and is essential in informing risk assessment methods for complex anti-androgenic mixtures in the aquatic environment.

Mixtures of endocrine disrupting contaminants modelled on human high end exposures: an exploratory study in rats.

By diminishing the action of androgens during gestation, certain chemicals can induce irreversible demasculinization and malformations of sex organs in the male rat after gestational exposure. Studies with mixtures of such anti-androgens have shown that substantial combined effects occur even though each individual chemical is present at low, ineffective doses, but the effects of mixtures modelled based on human intakes have not previously been investigated. To address this issue for the first time, we selected 13 chemicals for a developmental mixture toxicity study in rats where data about in vivo endocrine disrupting effects and information about human exposures was available, including phthalates, pesticides, UV-filters, bisphenol A, parabens and the drug paracetamol. The mixture ratio was chosen to reflect high end human intakes. To make decisions about the dose levels for studies in the rat, we employed the point of departure index (PODI) approach, which sums up ratios between estimated exposure levels and no-observed-adverse-effect-level (NOAEL) values of individual substances. For high end human exposures to the 13 selected chemicals, we calculated a PODI of 0.016. As only a PODI exceeding 1 is expected to lead to effects in the rat, a total dose more than 62 times higher than human exposures should lead to responses. Considering the high uncertainty of this estimate, experience on lowest-observed-adverse-effect-level (LOAEL)/NOAEL ratios and statistical power of rat studies, we expected that combined doses 150 times higher than high end human intake estimates should give no, or only borderline effects, whereas doses 450 times higher should produce significant responses. Experiments indeed showed clear developmental toxicity of the 450-fold dose in terms of increased nipple retention (NR) and reduced ventral prostate weight. The 150-fold dose group exhibited significantly increased NR. These observations suggest that highly exposed population groups, especially women of reproductive age, may not be protected sufficiently against the combined effects of chemicals that affect the hormonal milieu required for normal male sexual differentiation.

Constraining predictions of the carbon cycle using data.

We use a carbon-cycle data assimilation system to estimate the terrestrial biospheric CO(2) flux until 2090. The terrestrial sink increases rapidly and the increase is stronger in the presence of climate change. Using a linearized model, we calculate the uncertainty in the flux owing to uncertainty in model parameters. The uncertainty is large and is dominated by the impact of soil moisture on heterotrophic respiration. We show that this uncertainty can be greatly reduced by constraining the model parameters with two decades of atmospheric measurements.

Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat.

The incidence of hypospadias is increasing in young boys, but it remains unclear whether human exposure to endocrine disrupting chemicals plays a role. Risk assessment is based on estimation of no-observed-adverse-effect levels for single compounds, although humans are exposed to combinations of several anti-androgenic chemicals. In a mixture (MIX) study with three androgen receptor antagonists, vinclozolin, flutamide and procymidone, rats were gavaged during gestation and lactation with several doses of a MIX of the three chemicals or the chemicals alone. External malformations of the male reproductive organs were assessed on PND 47 using a score from 0 to 3 (normal to marked) for hypospadias. Markedly increased frequencies were observed after exposure to a MIX of the three chemicals compared to administration of the three chemicals alone. Anogenital distance at PND 1, nipple retention at PND 13, and dysgenesis score at PND 16 were highly correlated with the occurrence of hypospadias, and MIX effects were seen at doses where each of the individual chemicals caused no observable effects. Therefore, the results indicate that doses of anti-androgens, which appear to induce no hypospadias when judged on their own, may induce a very high frequency of hypospadias when they interact in concert with other anti-androgens.

Joint algal toxicity of 16 dissimilarly acting chemicals is predictable by the concept of independent action.

For a predictive assessment of the aquatic toxicity of chemical mixtures, two competing concepts are available: concentration addition and independent action. Concentration addition is generally regarded as a reasonable expectation for the joint toxicity of similarly acting substances. In the opposite case of dissimilarly acting toxicants the choice of the most appropriate concept is a controversial issue. In tests with freshwater algae we therefore studied the extreme situation of multiple exposure to chemicals with strictly different specific mechanisms of action. Concentration response analyses were performed for 16 different biocides, and for mixtures containing all 16 substances in two different concentration ratios. Observed mixture toxicity was compared with predictions, calculated from the concentration response functions of individual toxicants by alternatively applying both concepts. The assumption of independent action yielded accurate predictions, irrespective of the mixture ratio or the effect level under consideration. Moreover, results even demonstrate that dissimilarly acting chemicals can show significant joint effects, predictable by independent action, when combined in concentrations below individual NOEC values, statistically estimated to elicit insignificant individual effects of only 1%. The alternative hypothesis of concentration addition resulted in overestimation of mixture toxicity, but differences between observed and predicted effect concentrations did not exceed a factor of 3.2. This finding complies with previous studies, which indicated near concentration-additive action of mixtures of dissimilarly acting substances. Nevertheless, with the scientific objective to predict multi-component mixture toxicity with the highest possible accuracy, concentration addition obviously is no universal solution. Independent action proves to be superior where components are well known to interact specifically with different molecular target sites, and provided that reliable statistical estimates of low toxic effects of individual mixture constituents can be given. With a regulatory perspective, however, fulfilment of both conditions may be regarded as an extraordinary situation, and hence concentration addition may be defendable as a pragmatic and precautionary default assumption.

Water quality objectives for mixtures of toxic chemicals: problems and perspectives.

The need to develop water quality objectives not only for single substances but also for mixtures of chemicals seems evident. For that purpose, the conceptual basis could be the use of the two existing biometric models: concentration addition (CA) and independent action (IA), which is also called response addition. Both may allow calculation of the toxicity of mixtures of chemicals with similar modes of action (CA) or dissimilar modes of action (IA), respectively. The joint research project Prediction and Assessment of the Aquatic Toxicity of Mixtures of Chemicals (PREDICT) within the framework of the IVth Environment and Climate Programme of the European Commission, provided the opportunity to address (a) chemometric and QSAR criteria to classify substances as supposedly similarly or dissimilarly acting; (b) the predictive values of both models for the toxicity of mixtures at low, statistically nonsignificant effect concentrations of the individual components; and (c) the predictability of mixture toxicity at higher levels of biological complexity. In this article, the general outline, methodological approach, and some preliminary findings of PREDICT are presented. A procedure for classifying chemicals in relation to their structural and toxicological similarities has been developed. The predictive capabilities of CA and IA models have been demonstrated for single species and, to some extent, for multispecies testing. The role of very low effect concentrations in multiple mixtures has been evaluated. Problems and perspectives concerning the development of water quality objectives for mixtures are discussed.

Predicting the joint algal toxicity of multi-component s-triazine mixtures at low-effect concentrations of individual toxicants.

Herbicidal s-triazines are widespread contaminants of surface waters. They are highly toxic to algae and other primary producers in aquatic systems. This results from their specific interference with photosynthetic electron transport. Risk assessment for aquatic biota has to consider situations of simultaneous exposure to various of these toxicants. In tests with freshwater algae we predicted and determined the toxicity of multiple mixtures of 18 different s-triazines. The toxicity parameter was the inhibition of reproduction of Scenedesmus vacuolatus. Concentration-response analyses were performed for single toxicants and for mixtures containing all 18 s-triazines in two different concentration ratios. Experiments were designed to allow a valid statistical description of the entire concentration-response relationships, including the low concentration range down to EC1. Observed effects and effect concentrations of mixtures were compared to predictions of mixture toxicity. Predictions were calculated from the concentration-response functions of individual s-triazines by applying the concepts of concentration addition and independent action (response addition) alternatively. Predictions based on independent action tend to underestimate the overall toxicity of s-triazine mixtures. In contrast, the concept of concentration addition provides highly accurate predictions of s-triazine mixture toxicity, irrespective of the effect level under consideration and the concentration ratio of the mixture components. This also holds true when the mixture components are present in concentrations below their individual NOEC values. Concentrations statistically estimated to elicit non-significant effects of only 1% still contribute to the overall toxicity. When present in a multi-component mixture they can co-operate to give a severe joint effect. Applicability of the findings obtained with s-triazines to mixtures of other contaminants in aquatic systems and consequences for risk assessment procedures are discussed.

Assessing the biological potency of binary mixtures of environmental estrogens using vitellogenin induction in juvenile rainbow trout (Oncorhynchus mykiss).

Experiments were conducted to assess the in vivo potency of binary mixtures of estrogenic chemicals using plasma vitellogenin (VTG) concentrations in juvenile rainbow trout (Oncorhynchus mykiss) as the endpoint. The estrogenic potencies of estradiol-17beta (E2), 4-tertnonylphenol (NP), and methoxychlor (MXC) were determined following 14 day exposures to the individual chemicals and binary mixtures of these chemicals. E2, NP, and MXC all induced concentration dependent increases in plasma VTG, with lowest observed effect concentrations of 4.7 and 7.9 ng L(-1) for E2, 6.1 and 6.4 microg L(-1) for NP, and 4.4 and 6.5 microg L(-1) for MXC. Concentration-response curves for fixed ratio binary mixtures of E2 and NP (1:1000), E2 and MXC (1:1000), and NP and MXC (1:1) were compared to those obtained for the individual chemicals, using the model of concentration addition. Mixtures of E2 and NP were additive at the concentrations tested, but mixtures of E2 and MXC were less than additive. This suggests that while NP probably acts via the same mechanism as E2 in inducing VTG synthesis, MXC may be acting via a different mechanism(s), possibly as a result of its conversion to HPTE which is an estrogen receptor alpha agonist and an estrogen receptor beta antagonist. It was not possible to determine whether mixtures of MXC and NP were additive using VTG induction, because the toxicity of MXC restricted the effect range forwhich the expected response curve forthe binary mixture could be calculated. The data presented illustrate that the model of concentration addition can accurately predict effects on VTG induction, where we know that both chemicals act via the same mechanism in mediating a vitellogenic response.

Biomonitoring on carcinogenic metals and oxidative DNA damage in a cross-sectional study.

Oxidative DNA damage is mediated by reactive oxygen species and is supposed to play an important role in various diseases including cancer. The endogenous amount of reactive oxygen species may be enhanced by the exposure to genotoxic metals. A cross-sectional study was conducted from 1993 to 1994 in an urban population in Germany to investigate the association between metal exposure and oxidative DNA damage. The cross-sectional sample of 824 participants was recruited from the registry of residents in Bremen, comprising about two-third males and one-third females with an average age of 61.1 years. A standardized questionnaire was used to obtain the occupational and smoking history. The incorporated dose of exposure to metals was assessed by biological monitoring. Chromium, cadmium, and nickel were measured in 593 urine samples. Lead was determined in blood samples of 227 participants. As a biomarker for oxidative DNA damage, 7,8-dihydro-8-oxoguanine has been analyzed in lymphocytes of 201 participants. Oxidative lesions were identified by single strand breaks induced by the bacterial formamidopyrimidine-DNA glycosylase (Fpg) in combination with the alkaline unwinding approach. The concentrations of metals indicate a low body load (median values: 1.0 microg nickel/l urine, 0.4 microg cadmium/l urine, and 46 microg lead/l blood; 83% of chromium measures were below the technical detection limit of 0.3 microg/l). The median level of Fpg-sensitive DNA lesions was 0.23 lesions/10(6) bp. A positive association between nickel and the rate of oxidative DNA lesions (Fpg-sensitive sites) was observed (odds ratio, 2.15; tertiles 1 versus 3, P < 0.05), which provides further evidence for the genotoxic effect of nickel in the general population.