[Evaluating health risk tolerance and risk assessment]. / Gesundheitsverträglichkeitsprüfung und Risikobewertung.

According to current regulations, major projects are subject to an environmental impact assessment. Within this framework, not only ecological criteria have to be met, but also the possible health impact for the exposed population must assessed. In the absence of limit values for carcinogenic substances in the air, the health impact assessment can be based on quantitative risk assessment. This technology was formerly developed for the assessment of cancer risk imposed by existing environmental exposures, but it is also suitable for the prediction of future exposures and their health consequences. This is demonstrated by using a planned toxic waste incinerator as a model.

A cluster of childhood leukaemias near two neighbouring nuclear installations in Northern Germany: prevalence of chromosomal aberrations in peripheral blood lymphocytes.

PURPOSE: Between 1990 and 1991 a leukaemia cluster was observed in children living close to the combined site of a nuclear power plant and a nuclear research facility in Elbmarsch, a region in Lower Saxony (Germany). We aim to investigate the prevalence of presumably radiation-induced chromosomal aberrations in peripheral blood lymphocytes of children in Elbmarsch and children of a control region in order to find out whether there was an uncontrolled release of radioactive material which resulted in a substantial exposure. MATERIALS AND METHODS: The frequency of dicentric and ring chromosomes in lymphocytes of the peripheral blood in 42 children in Elbmarsch and 30 children in Plön was investigated. Children in both groups had been permanent residents of the study area. RESULTS: The mean frequency of dicentric and ring chromosomes in Elbmarsch was 14/32580 cells (=0.430 x 10(-3); 95% CI 0.24-0.70 x 10(-3) cells), and in Plön it was 17/24065 cells (=0.706 x 10(-3); 95% CI 0.42-1.10 x 10(-3) cells). CONCLUSIONS: No difference in the frequency of dicentric and ring chromosomes was observed between children in Elbmarsch living close to a combined site of a nuclear power plant and a nuclear research facility and children living in the control area Plön. The power of the study to detect a threefold or higher increase in the aberration frequency was at least 0.86.

[Concepts for the regulation of mixtures of toxic pollutants in environmental hygiene]. / Regulierungskonzepte für Schadstoffgemische in der Umwelthygiene.

In view of the increasing accumulation of large-scale livestock production facilities in the western parts of Lower Saxony the question rises how ecology and economy can be conciliated and how the protection of human health can be assured. Based on existing legislation this is hard to achieve because of the weak legal position of the administration when trying to prohibit the further expansion of livestock production as opposed to the strong legal position of owners and investors. Presently there is no agreement within the scientific community on safe limits for airborne pathogens and it is quite obvious that thresholds for peak concentrations do not solve the problem of background level exposures. Apart from the unsatisfactory current practise to licence farm animal units in the outskirts of existing villages only, in future the introduction of the EC Environmental Management and Auditing Scheme (EMAS) in animal production may improve the situation. This management system is intended to permanently reduce the environmental impact of a production site and implements the ALARA-PRINCIPLE (as low as reasonably achievable) which is known from protection measures against radiation. As the implementation of the EMAS so far works only on a voluntary basis, an incentive is needed. If dealers and consumers give preference to products from producers having adopted the EMAS, this would be a very efficient incentive. Before this could be put into practise, however, the EMAS criteria originally designed for industrial production sites will have to be adapted to the special conditions of animal production.

[Blood PCDD/F levels in blood of residents of a former cable incineration facility]. / PCDD/F-Gehalte im Blut von Anwohnern einer früheren Kabelabbrennanlage.

Increased levels of polychlorinated dibenzo-p-dioxins (PCDD) and dibenzofuranes (PCDF) were found in soil and roof dust of a residential area located near a metal reclamation plant in Northern Germany. In order to assess the degree of exposure of persons residing near to this plant, venous blood samples were collected from 14 subjects and analysed for PCDD/F and fat content. Furthermore, blood samples collected from the members of a farmer's family living nearby were analysed for PCDD/F. Previous studies had shown significantly increased PCDD/F levels in chicken eggs produced on this farm. Regarding the group of residents, the PCCD/F levels in blood fat were not increased when compared to background levels. However, some members of the farmer's family had increased PCDD/F levels in blood fat. The findings of these studies suggest that long-term consumption of contaminated animal products, especially chicken eggs, may result in increased PCDD/F levels in the body, whereas increased levels of PCDD/F in dust and soil do not noticeably affect the PCDD/F levels in human blood fat.

[Methods of risk assessment from data of experimental carcinogenesis studies]. / Methoden der Risikoabschätzung aus Daten experimenteller Kanzerogenitätsuntersuchungen.

A comparison of the carcinogenic potencies of different substances and an assessment of the risk to exposed people can contribute significantly to the management of carcinogenic hazards including adequate regulatory decisions. A mathematical estimation of the risk caused by a certain height of exposure is usually done under the assumption of a linear dose-response relationship by means of an arithmetical factor which gives the ratio of risk to dose in the low-response range and which has to be found on the basis of epidemiological or experimental data. This work deals with calculations of risk/dose ratios from the data of three carcinogenicity tests by means of statistical methods. The influence of the selection of mathematical model, background assumption and the point of the function chosen for the calculation of the ratio was tested. The results show that an additivity assumption for the background leads to linearity of the curve in the low-response range such that the ratios calculated with different models (multistage, weibull, logit, probit) or for different points of the functions do not differ significantly within the data sets tested. Even under the assumption of independence of the background risk the influence of the model selected is still small if the ratios are calculated for the lowest experimental dose or for an exposure associated risk of 1%. Risk/dose ratios calculated by one of these methods utilize the information of several experimental groups. They seem to be well suited for a direct comparison of the potency of different carcinogens and as a basis for an assessment of the carcinogenic risk to humans, which can serve as a measure of the hazard of a single exposed person or may give an idea about the tumour incidences to be expected within an exposed population.

Neurotoxic substances also posing a cancer risk: a warning.

A large proportion of compounds studied for their neurotoxic potential are at the same time suspected or proven carcinogens. This is demonstrated using the International Neurotoxicology Association (INA) Professional Interest Directory and publications from the field of neurotoxicology as examples. In addition to listing these compounds, the classification scheme used by the International Agency for Research on Cancer (IARC), the Commission of the European Communities (EC), the U.S. Environmental Protection Agency (EPA), the German MAK-Commission of the Deutsche Forschungsgemeinschaft (DGF) and the U.S. National Institute of Occupational Safety and Health (NIOSH) to make qualitative risk assessments is explained. Finally, a short initiation to quantitative risk assessment as performed by the US EPA and the World Health Organization (WHO) is given in order to put the reader into a position as to assess the cancer risk incurred by his/her co-workers and by himself.

The action of thallium on the excitability of CA1 pyramidal cells in hippocampal slices.

The effect of thallium ions on central neuronal activity was investigated in hippocampal slice preparations from guinea pigs and rats using extra- and intracellular recording techniques. Thallium induced a reversible and concentration-dependent reduction of the orthodromically evoked compound action potential of CA1 pyramidal cells with only weak effects on either afferent fiber activity, postsynaptic potentials or antidromically evoked responses. The membrane potential and input resistance of the pyramidal cells were not impaired by thallium. In contrast, variations in the maintained spike activity and spontaneously occurring inhibitory postsynaptic potentials were observed. It is concluded, that in contrast to its presynaptic action in the peripheral nervous system, thallium has a predominant postsynaptic target site in the hippocampal slice preparation. It is suggested that the neurotoxic action of thallium is not mediated by an interaction with specific ion channels of the cell membrane, but rather by an unspecific influence on the intracellular metabolism of the CA1 pyramidal cell.

Health effects during a smog episode in West Germany in 1985.

In January 1985 a smog period occurred for 5 days in parts of West Germany, including the Rhur District. Mortality (24,000 death certificates), morbidity in hospitals (13,000 hospital admissions, 5400 outpatients, 1500 ambulance transports) and consultations in doctors' offices (1,250,000 contacts) were studied for a 6-week period including the smog episode and a time interval before and thereafter. The study region was the State of North Rhine-Westfalia (16 million inhabitants), but the analysis is restricted to the comparison of the polluted area and a control area (6 million inhabitants each). During the smog period, mortality and morbidity in hospitals increased in the polluted area, but there was no substantial increase in the control area. The increases were for the total number of deaths 8 vs. 2% (polluted area vs. control area), for hospital admissions 15 vs. 3%, for outpatients 12 vs. 5% and for deliveries by ambulance to hospitals 28% in the polluted area (not investigated in the control area). The effects were more pronounced for cardiovascular diseases than for respiratory diseases. The consultations in doctors' offices show a slight decrease (-2 vs. -4%). Regression analysis shows a moderate influence of temperature, but a strong influence of ambient air pollution. The maxima of the ambient concentrations are more important on the same day, whereas the influence of the daily averages is more pronounced after a delay of 2 days. The results are discussed considering other possible confounders such as indoor pollution and psychogenic influences of the alarm situation. In total, the study suggests moderate health effects due to increased air pollution during the smog episode.

Risk modelling: which models to choose?

Using as examples excess lung cancer mortality in coke oven workers and lung tumor induction in rats by inhalation of diesel engine emissions or cadmium chloride aerosol, the maximum likelihood estimate and the upper limit of risk were determined using a set of conventional risk models. The additional safety offered by going to the upper limit of the 95% confidence interval when deriving a unit risk value was found to be less than a factor of 5 in all but one case, and usually much less than 2. It is concluded that the selection of an adequate model is the most critical step in risk assessment, and that an additional safety factor may be required to allow for a better protection of the public in case models other than the most conservative ones come into use.

Miniature endplate potentials as a tool in neurotoxicology.

The toxic effect of thallium added to the bath solution was studied with intra- and extracellular recordings from mammalian nerve-muscle preparations. To elucidate the target region, 3 different functional parameters were studied: (1) Post-synaptic endplate potentials (EPPs) resulting from evoked transmitter release; (2) Post-synaptic miniature endplate potentials (MEPPSs) resulting from spontaneous transmitter release; and (3) Presynaptic ion currents at the nerve terminal. At a concentration of 0.5 mM/l thallium acetate, EPP amplitudes were irreversibly decreased while MEPP amplitudes remained unaffected. MEPP frequencies were reversibly increased, indicating a presynaptic rather than a post-synaptic target site of thallium toxicity. The subpopulation of small MEPPs (sub-MEPPs) behaved like the MEPP population, except that upon addition of 4-AP, the sub-MEPP population was augmented at the cost of the MEPP population. In view of the slow time course of the toxic effects (30 min for a 10-fold increase of MEPP frequency, 100-180 min for a 50% reduction of EPP amplitudes), it is concluded that thallium needs to be transported across the cell membrane before it finally interferes with release mechanisms. It is hypothesised that thallium reduces the number of active sites recruited by one action potential (reduced EPP amplitude), while at the same time the probability of transmitter liberation is enhanced (increased MEPP frequency). The rather indirect mode of action of thallium was also found when presynaptic ion currents were recorded using extracellular electrodes. In proportion to the decrease of the EPP amplitudes, a reduction of all inward and outward currents was observed. This effect was also irreversible. It is concluded that in spite of some similarities, thallium behaves quite differently from bivalent heavy metals like cobalt and cadmium, which act as competitive calcium antagonists at the presynaptic nerve terminal. In these toxic substances, the time course of intoxication is much faster, the required concentration is much lower, and the inhibition of the slow calcium current is reversible.

Detection of sub-miniature endplate potentials by harmonic analysis.

In phrenic nerve-diaphragm preparations from young rats and mice, long-term recordings of miniature endplate potentials (MEPPs) from single synapses were performed. Amplitude histograms obtained from these experiments were analysed with respect to the presence of multiple peaks which are believed to reflect quantal transmitter release. This was accomplished by subjecting MEPP amplitude histograms as well as matched random number histograms to Fourier analysis; harmonics in the MEPP amplitude distribution were considered valid only if they exceeded those of the random number distribution. In 9 out of 11 experiments, substantial evidence for the existence of preferred amplitudes was obtained; in two cases, however, it was completely missing. Applying our method to a series of promising MEPP amplitude histograms selected from the literature, we found a similar relationship between positive and negative results. We also noted a fairly constant relationship between the size of the elementary sub-MEPPs and the mean amplitude of the bell-MEPPs, named so according to the Gaussian shape of their amplitude distribution.

The action of thallium acetate on spontaneous transmitter release in the rat neuromuscular junction.

Frequencies and amplitudes of miniature endplate potentials (MEPP's) were recorded from neuromuscular junctions of the rat phrenic nerve-diaphragm preparation in vitro. Superfusion of the preparations with Ringer solution containing thallium acetate (Tlac) gradually increased the frequency of MEPP's by a factor of 10 within 30 min (1 X 10(-3) mol/l Tlac) and 180 min (5 X 10(-4) mol/l Tlac), whereas the amplitude of MEPP's remained unchanged. Frequency of MEPP's fitted a Poisson-distribution which persisted during superfusion with Tl+-Ringer. Sub-MEPP amplitudes remained unaffected by the action of thallium. It is concluded that thallium interferes presynaptically with spontaneous transmitter release.

The action of thallium acetate on neuromuscular transmission in the rat phrenic nerve-diaphragm preparation.

In the isolated phrenic nerve-hemidiaphragm preparation from the rat, thallium acetate induced a dose-dependent irreversible paralysis. There was a major time lag between the onset of the exposure and the decline in the indirectly elicited muscle twitches. The slope of the decline was in proportion to the applied concentration, which ranged from 1 X 10(-3) to 5 X 10(-6) mol/l. The paralysis was definitively manifest after approximately 40 min of incubation. In the phase of paralysis, both electrical stimulation of the muscle and chemical stimulation by addition of K+ were fully effective. However, addition of 4-aminopyridine and/or guanidine restored the indirect muscle twitches, indicating a previous reduction of synaptic activity by thallium. Lowering the Ca2+-concentration resulted in a reduced paralysis time. From these results it is suggested that thallium interferes with synaptic transmission by presynaptically antagonizing Ca2+-dependent processes.

Effects of heavy metals (Cd, Tl, Zn and Pb) on glial cells.

This communication deals with an ultrastructural assay of certain quantitative brain parameters susceptible to be modified during heavy metal intoxication. It particularly focusses on the changes in the populations of glial cells which appear as a most sensitive morphological indicator of brain poisoning.