Hazards from chemicals: scientific questions and conflicts of interest.

All substances are toxic when the dose is large enough. In order to regulate the use of chemicals, we need to measure the level at which toxic effects are found. Epidemiological evidence suggests that present levels of chemical use do not lead to widespread harmful contamination of the human environment. For chemicals, most of the problems of toxicity are found in the workplace, while the population at large gets most of its toxic effects from voluntary exposure to substances such as tobacco smoke and ethanol. The prevention and control of toxic effects depends on a series of steps. This begins with measurement of toxicity in model systems, such as laboratory animals, and the estimation of the likely exposure of workers or consumers. Reliable extrapolation of information gathered from animals to the diverse and biochemically differing human population depends on understanding mechanisms of toxic effects. The toxic effect and mechanisms of action of substances such as carbon tetrachloride or paracetamol have been extensively investigated, and our ability to predict toxicity or develop antidotes to poisoning has had some success, but epidemiology is still an essential part of assessment of toxic effects of new chemicals. The example of phenobarbitone shows how animal experiments may well lead to conclusions which do not apply to man. After measurement of toxicity and assessment of likely hazards in use comes the final evaluation of the use of a chemical. This depends not only on its toxicity, but also on its usefulness. The direct effects on health may be small in comparison with the indirect advantageous effects which a useful substance such as vinyl chloride may bring. The assessment of risks and benefits of new chemicals can be partly removed from a political style of discourse, but the evaluation of the relative weight to be attached to these risks and benefits is inescapably political. The scientific contribution must be to allow the debate to take place in the light of maximum clarity of information about the consequences of use of chemicals.     

Approaches for the development of occupational exposure limits for man-made mineral fibres (MMMFs)

Occupational exposure limits (OELs) are an essential tool in the control of exposure to hazardous chemical agents, and serve to minimise the occurrence of occupational diseases associated with such exposure. The setting of OELs, together with other associated measures, forms an essential part of the European Community's strategy on health and safety at work, upon which the legislative framework for the protection of workers from risks related to chemical agents is based. The European Commission is assisted by the Scientific Committee on Occupational Exposure Limits (SCOEL) in its work of setting OELs for hazardous chemical agents. The procedure for setting OELs requires information on the toxic mechanisms of an agent that should allow to differentiate between thresholded and non-thresholded mechanisms. In the first case, a no-observed adverse effect level (NOAEL) can be defined, which can be the basis for a derivation of an OEL. In the latter case, any exposure is correlated with a certain risk. If adequate scientific data are available, SCOEL estimates the risk associated with a series of exposure levels. This can then be used for guidance, when setting OELs at European level. Man-made mineral fibres (MMMFs) are widely used at different worksites. MMMF products can release airborne respirable fibres during their production, use and removal. According to the classification of the EU system, all MMMF fibres are considered to be irritants and are classified for carcinogenicity. EU legislation foresees the use of limit values as one of the provisions for the protection of workers from the risks related to exposure to carcinogens. In the following paper, the research requirements identified by SCOEL for the development of OELs for MMMFs will be presented.     

Does the Emperor Have Any Clothes: Using Mechanistic Information or Doing Houdini Risk Assessments?

Risk assessment research rarely quells controversy. Mega-mouse, and mega-rat, experiments contradicted a threshold for carcinogenesis, yet thresholds are still argued. High to low dose continuity of response from cigarette smoking to environmental tobacco smoke, and from occupational asbestos exposure to take-home asbestos, contradict thresholds in people. Nevertheless, mechanistic hypotheses allege “Houdini Risk Assessments”, which make risks disappear or allow industries to escape from protecting workers. Despite concerns for animal-to-human extrapolations, priority occupational exposures with sufficient or substantial evidence of carcinogenicity in people not addressed by new exposure limits include silica, sulfuric acid mist, chromates, diesel particulate matter, particulate matter generally, metalworking fluids, welding fume, and formaldehyde. “Houdini Risk Assessments” are exercises in “anti-hypothesis generation”: ignore selected tumor sites and types; ignore data from people (as with formaldehyde and diesel); choose the most resistant species in laboratory tests; select biochemical parameters in which the most resistant species resembles people; assume a mechanism that gives threshold or steep exposure response for carcinogenic effect; and reduce estimated people risk by the parameter ratio to the most resistant species. NORA research should focus on quantitative reconciliation of laboratory and epidemiology studies, and develop a counter “anti-hypothesis” generation research agenda for key exposure circumstances.     

Risk assessment of neurotoxic pesticides

In order to establish safe exposure levels for toxic chemicals, risk assessment guidelines have been developed. A compilation is given by the author on the elements of risk assessment of hazardous neurotoxic pesticides, using data obtained from human epidemiological studies, from animal experiments, from the international literature and from the author's own experiments as well. Well-controlled laboratory studies of neurotoxicity have the potential to provide adequate exposure and effect data for accurate hazard identification. Animal models of neurotoxicity as highly sensitive behavioral and neurophysiological methods as a function of doses, provide data for human low dose extrapolation by using mathematical models. This procedure might be the basis for reducing risk ("risk management"), therefore some examples are given, how to handle properly neurotoxic pesticides with different- high or low-risk.     

An Ecological Risk Assessment Framework for Effects of Onsite Wastewater Treatment Systems and Other Localized Sources of Nutrients on Aquatic Ecosystems

An ecological risk assessment framework for onsite wastewater treatment systems and other localized sources of nutrients is presented, including problem formulation, characterization of exposure, characterization of effects, and risk characterization. The framework is most pertinent to the spatial scale of residential treatment systems located adjacent to small ponds, streams, or lagoons and some parts of shallow estuaries. Freshwater and estuarine ecosystems are distinguished based on differences in nutrient dynamics. Phosphorus exposure is the major determinant of phytoplankton production in most North American lakes. Nitrate can be directly toxic to aquatic biota such as amphibians. In shallow estuaries or lagoons, nitrogen is the primary stressor, which can be directly toxic to vegetation or can interact with biota to produce secondary stressors (limited light penetration, oxygen limitation, reduction in habitat, or reduction in forage vegetation or prey). Algal production, macrophyte production, fish community abundance and production, benthic community abundance and production, and amphibian community abundance and production are examples of risk assessment endpoint properties. Models and measurement methods for the characterization of exposure and effects are discussed, as well as sources and quantification of uncertainty. Example weight-of-evidence tables are presented for failure scenarios involving traditional and emerging onsite wastewater system technologies.     

Dose and dose rate extrapolation factors for malignant and non-malignant health endpoints after exposure to gamma and neutron radiation

Murine experiments were conducted at the JANUS reactor in Argonne National Laboratory from 1970 to 1992 to study the effect of acute and protracted radiation dose from gamma rays and fission neutron whole body exposure. The present study reports the reanalysis of the JANUS data on 36,718 mice, of which 16,973 mice were irradiated with neutrons, 13,638 were irradiated with gamma rays, and 6107 were controls. Mice were mostly Mus musculus, but one experiment used Peromyscus leucopus. For both types of radiation exposure, a Cox proportional hazards model was used, using age as timescale, and stratifying on sex and experiment. The optimal model was one with linear and quadratic terms in cumulative lagged dose, with adjustments to both linear and quadratic dose terms for low-dose rate irradiation (<5 mGy/h) and with adjustments to the dose for age at exposure and sex. After gamma ray exposure there is significant non-linearity (generally with upward curvature) for all tumours, lymphoreticular, respiratory, connective tissue and gastrointestinal tumours, also for all non-tumour, other non-tumour, non-malignant pulmonary and non-malignant renal diseases (p < 0.001). Associated with this the low-dose extrapolation factor, measuring the overestimation in low-dose risk resulting from linear extrapolation is significantly elevated for lymphoreticular tumours 1.16 (95% CI 1.06, 1.31), elevated also for a number of non-malignant endpoints, specifically all non-tumour diseases, 1.63 (95% CI 1.43, 2.00), non-malignant pulmonary disease, 1.70 (95% CI 1.17, 2.76) and other non-tumour diseases, 1.47 (95% CI 1.29, 1.82). However, for a rather larger group of malignant endpoints the low-dose extrapolation factor is significantly less than 1 (implying downward curvature), with central estimates generally ranging from 0.2 to 0.8, in particular for tumours of the respiratory system, vasculature, ovary, kidney/urinary bladder and testis. For neutron exposure most endpoints, malignant and non-malignant, show downward curvature in the dose response, and for most endpoints this is statistically significant (p < 0.05). Associated with this, the low-dose extrapolation factor associated with neutron exposure is generally statistically significantly less than 1 for most malignant and non-malignant endpoints, with central estimates mostly in the range 0.1–0.9. In contrast to the situation at higher dose rates, there are statistically non-significant decreases of risk per unit dose at gamma dose rates of less than or equal to 5 mGy/h for most malignant endpoints, and generally non-significant increases in risk per unit dose at gamma dose rates ≤5 mGy/h for most non-malignant endpoints. Associated with this, the dose-rate extrapolation factor, the ratio of high dose-rate to low dose-rate (≤5 mGy/h) gamma dose response slopes, for many tumour sites is in the range 1.2–2.3, albeit not statistically significantly elevated from 1, while for most non-malignant endpoints the gamma dose-rate extrapolation factor is less than 1, with most estimates in the range 0.2–0.8. After neutron exposure there are non-significant indications of lower risk per unit dose at dose rates ≤5 mGy/h compared to higher dose rates for most malignant endpoints, and for all tumours (p = 0.001), and respiratory tumours (p = 0.007) this reduction is conventionally statistically significant; for most non-malignant outcomes risks per unit dose non-significantly increase at lower dose rates. Associated with this, the neutron dose-rate extrapolation factor is less than 1 for most malignant and non-malignant endpoints, in many cases statistically significantly so, with central estimates mostly in the range 0.0–0.2.     

Human exposure to endocrine disrupters: carcinogenic risk assessment

Human exposure to endocrine disrupters (EDs) is widespread and is considered to pose a growing threat to human health. Recent advances in molecular and genetic research and better understanding of mechanisms of blastic cell transformation have led to efforts to improve cancer risk assessment for populations exposed to this family of xenobiotics. In risk assessment, low dose extrapolation of cancer incidence data from both experimental animals and epidemiology studies has been largely based on models assuming linear correlation at low doses, despite existence of evidence showing otherwise. Another weakness of ED risk assessment is poor exposure data in ecological studies. Those are frequently rough estimates derived from contaminated items of local food basket surveys. Polyhalogenated hydrocarbons are treated as examples. There is growing sense of urgency to develop a biologically based dose response model of cancer risk, integrating emerging data from molecular biology and epidemiology to provide more realistic data for risk assessors, public, public health managers and environmental issues administrators.     

A dose-response model incorporating nonlinear kinetics

This paper introduces a dose-response model for toxic quantal response data based on hit theory applied to the dose unit as transformed by a nonlinear kinetic equation. When spontaneous background response is included in the model, the resulting dose-response model has four parameters. The maximum likelihood estimators and their large-sample properties are given. Likelihood ratio tests of interest are developed, including one for whether the model is one-hit in the transformed dose and one to check whether nonlinear kinetics is operative. The use of the model for low-dose extrapolation is presented. Finally, the procedures developed are illustrated on data from three animal carcinogenicity bioassays that show, respectively, concave, linear, and convex dose-response curves in the observed data.     

Cellular pathways for DNA repair and damage tolerance of formaldehyde-induced DNA-protein crosslinks

Although it is well established that DNA-protein crosslinks are formed as a consequence of cellular exposure to agents such as formaldehyde, transplatin, ionizing and ultraviolet radiation, the biochemical pathways that promote cellular survival via repair or tolerance of these lesions are poorly understood. To investigate the mechanisms that function to limit DNA-protein crosslink-induced cytotoxicity, the Saccharomyces cerevisiae non-essential gene deletion library was screened for increased sensitivity to formaldehyde exposure. Following low dose, chronic exposure, strains containing deletions in genes mediating homologous recombination showed the greatest sensitivity, while under the same exposure conditions, deletions in genes associated with nucleotide excision repair conferred only low to moderate sensitivities. However, when the exposure regime was changed to a high dose acute (short-term) formaldehyde treatment, the genes that conferred maximal survival switched to the nucleotide excision repair pathway, with little contribution of the homologous recombination genes. Data are presented which suggest that following acute formaldehyde exposure, repair and/or tolerance of DNA-protein crosslinks proceeds via formation of nucleotide excision repair-dependent single-strand break intermediates and without a detectable accumulation of double-strand breaks. These data clearly demonstrate a differential pathway response to chronic versus acute formaldehyde exposures and may have significance and implications for risk extrapolation in human exposure studies.     

Predicting cancer rates in astronauts from animal carcinogenesis studies and cellular markers

The radiation space environment includes particles such as protons and multiple species of heavy ions, with much of the exposure to these radiations occurring at extremely low average dose-rates. Limitations in databases needed to predict cancer hazards in human beings from such radiations are significant and currently do not provide confidence that such predictions are acceptably precise or accurate. In this article, we outline the need for animal carcinogenesis data based on a more sophisticated understanding of the dose-response relationship for induction of cancer and correlative cellular endpoints by representative space radiations. We stress the need for a model that can interrelate human and animal carcinogenesis data with cellular mechanisms. Using a broad model for dose-response patterns which we term the "subalpha-alpha-omega (SAO) model", we explore examples in the literature for radiation-induced cancer and for radiation-induced cellular events to illustrate the need for data that define the dose-response patterns more precisely over specific dose ranges, with special attention to low dose, low dose-rate exposure. We present data for multiple endpoints in cells, which vary in their radiosensitivity, that also support the proposed model. We have measured induction of complex chromosome aberrations in multiple cell types by two space radiations, Fe-ions and protons, and compared these to photons delivered at high dose-rate or low dose-rate. Our data demonstrate that at least three factors modulate the relative efficacy of Fe-ions compared to photons: (i) intrinsic radiosensitivity of irradiated cells; (ii) dose-rate; and (iii) another unspecified effect perhaps related to reparability of DNA lesions. These factors can produce respectively up to at least 7-, 6- and 3-fold variability. These data demonstrate the need to understand better the role of intrinsic radiosensitivity and dose-rate effects in mammalian cell response to ionizing radiation. Such understanding is critical in extrapolating databases between cellular response, animal carcinogenesis and human carcinogenesis, and we suggest that the SAO model is a useful tool for such extrapolation.     

How do herbivorous insects cope with noxious secondary plant compounds in their diet?

Herbivorous insects use a variety of physiological mechanisms to cope with noxious (i.e., unpalatable and/or toxic) compounds in their food plants. Here, I review what is known about this coping process, focusing on one species of caterpillar, the tobacco hornworm (Manduca sexta). Herbivorous insects possess both preingestive (i.e., chemosensory) and postingestive response mechanisms for detecting plant secondary compounds. Stimulation of either class of detection mechanism inhibits feeding rapidly by reducing biting rate and/or bite size. This aversive response is highly adaptive during encounters with secondary plant compounds that are toxic. The insect's dilemma is that many harmless or mildly toxic compounds also activate the aversive response. To overcome this dilemma, herbivorous insects employ at least three mechanisms for selectively deactivating their aversive response to relatively harmless secondary plant compounds: (1) the presence of carbohydrates can mask the unpalatable taste of some secondary plant compounds; (2) prolonged dietary exposure to some unpalatable secondary plant compounds can initiate long-term adaptation mechanisms in the peripheral and central gustatory system; and (3) dietary exposure to toxic compounds can induce production of P450 detoxication enzymes. Thus, herbivorous insects utilize an integrated suite of physiological mechanisms to detect potentially toxic compounds in foods, and then selectively adapt to those that do not pose a serious threat to their growth and survivorship.     

U.S. Environmental Protection Agency's revised guidelines for carcinogen risk assessment: evaluating a postulated mode of carcinogenic action in guiding dose–response extrapolation

There are new opportunities to using data from molecular and cellular studies in order to bring together a fuller biological understanding of how chemicals induce neoplasia. In 1996, the Environmental Protection Agency (EPA) published a proposal to replace its 1986 Guidelines for Carcinogen Risk Assessment to take advantage of these new scientific advances in cancer biology. The analytical framework within the new guidelines focuses on an understanding of the mode of carcinogenic action. Mode of action data come into play in a couple of ways in these new guidelines. For example, such information can inform the dose–response relationship below the experimental observable range of tumours. Thus, mode of action data can be useful in establishing more appropriate guidance levels for environmental contaminants. It is the understanding of the biological processes that lead to tumour development along with the response data derived from experimental studies that can help discern the shape of the dose–response at low doses (linear vs. nonlinear). Because it is experimentally difficult to establish “true thresholds” from others with a nonlinear dose–response relationship, the proposed guidelines take a practical approach to depart from low-dose linear extrapolation procedures when there is sufficient experimental support for a mode of action consistent with nonlinear biological processes (e.g., tumours resulting from the disruption of normal physiological processes).     

The effects of neutrons in Hiroshima. Implications for the risk estimates

Risk estimates for radiation-induced late effects are relevant to various considerations in radiation protection. Most of these considerations relate to small doses for which no excess risk can be seen even in extensive epidemiological studies. Risk coefficients for radiation protection must, therefore, be based on uncertain extrapolation of observations obtained at moderate or high doses. The extrapolation can not be replaced, as yet, by new, more direct information on processes such as radiation-induced genetic instability or adaptive response. While the new findings indicate complexities that may be highly relevant to the effectiveness- or lack of effectiveness- of radiation at low doses, they remain insufficiently understood to permit a decision as to whether dose-effect relations are linear, curvilinear, or have a threshold in dose. In view of these uncertainties radiation-protection regulations are, today, based on the conservative assumption of a linear dose dependence without threshold. This approach assures a sufficient degree of protection, but it may become unreasonably over-conservative, when the cautious hypothesis is treated as proven fact, and when-in addition-the assumed initial slope of the dose relation is not critically evaluated. A reliable evaluation needs to be based on the follow-up of the atom-bomb bomb survivors, and several major aspects of current interest are discussed here. a) Mortality from solid tumours in Hiroshima shows a statistically significant excess at a colon dose of 50 mGy; however, it is likely that this is the result of a bias in assigning causes of death. b) The solid cancer mortality data of the atom-bomb survivors are consistent with linearity in dose, but they can be shown to be equally consistent with a considerable degree of curvature. c) Even with the present dosimetry system, DS86, a substantial part of the effect at small doses in Hiroshima could be due to neutrons. If this is the case, the risk estimates for gamma-rays need to be accordingly decreased. d) Numerous neutron-activation measurements in Hiroshima indicate that the DS86 underestimates the neutron doses. The evidence is, up to now, based only on activation products of low energy neutrons, but efforts are currently underway to determine activation products of high energy neutrons. If these measurements should substantiate the present trend, the cancer data in Hiroshima would cease to be reliable proof of an effect of gamma-rays at low doses. Instead the dose dependence for gamma-rays could be purely quadratic, and any initial slope in the linear-quadratic dependence might well be attributable to neutrons only.     

Toxicity of depleted uranium complexes is independent of p53 activity

The p53 tumor suppressor protein is one of the key checkpoints in cellular response to a variety of stress mechanisms, including exposure to various toxic metal complexes. Previous studies have demonstrated that arsenic and chromium complexes are able to activate p53, but there is a dearth of data investigating whether uranium complexes exhibit similar effects. The use of depleted uranium (DU) has increased in recent years, raising concern about DU's potential carcinogenic effects. Previous studies have shown that uranyl acetate and uranyl nitrate are capable of inducing DNA strand breaks and potentially of inducing oxidative stress through free radical generation, two potential mechanisms for activation of p53. Based on these studies, we hypothesized that either uranyl acetate or uranyl nitrate could act as an activator of p53. We tested this hypothesis using a combination of cytotoxicity assays, p53 activity assays, western blotting and flow cytometry. All of our results demonstrate that there is not a p53-mediated response to either uranyl acetate or uranyl nitrate, demonstrating that any cellular response to uranium exposure likely occurs in a p53-independent fashion under the conditions studied.     

Cellular Stress Responses,Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes

The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. A prediction of this theory is that, among species, differential rates of aging may be apparent on the basis of intrinsic differences in oxidative damage accrual. Although widely accepted, there is a growing number of exceptions to this theory, most contingently related to genetic model organism investigations. Proteins are one of the prime targets for oxidative damage and cysteine residues are particularly sensitive to reversible and irreversible oxidation. The adaptation and survival of cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response pathways and chaperone networks related to protein quality control and stability. The toxic effects that stem from the misassembly or aggregation of proteins or peptides, in any cell type, are collectively termed proteotoxicity. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress which increases in cancer, metabolic and neurodegenerative diseases. Pharmacological modulation of cellular stress response pathways has emerging implications for the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. A critical key to successful medical intervention is getting the dose right. Achieving this goal can be extremely challenging due to human inter-individual variation as affected by age, gender, diet, exercise, genetic factors and health status. The nature of the dose response in and adjacent to the therapeutic zones, over the past decade has received considerable advances. The hormetic dose–response, challenging long-standing beliefs about the nature of the dose–response in a lowdose zone, has the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses, including carnitines. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including the possible signaling mechanisms by which the carnitine system, by interplaying metabolism, mitochondrial energetics and activation of critical vitagenes, modulates signal transduction cascades that confer cytoprotection against chronic degenerative damage associated to aging and neurodegenerative disorders.     

Extrapolation from in vitro tests to human risk: experience with sodium fluoride clastogenicity

Genotoxic effects observed in vitro, only at high doses or high levels of cytotoxicity, will be false positives if such conditions are not achieved or cannot be tolerated in vivo. However, for such effects to be disregarded there must be a threshold dose or level of cytotoxicity below which genotoxicity is absent. Sodium fluoride (NaF) has previously been shown to be clastogenic in vitro in Syrian hamster cells and human fibroblasts. We have extended these studies in human fibroblasts and included a positive control (mitomycin C, MMC) which is clastogenic in vivo and carcinogenic, and a chemically related control (NaCl). Cytotoxicity was measured as mitotic inhibition and cell death (loss of clonogenicity). The results are used to illustrate the problems associated with quantitative extrapolation from in vitro tests to human risk, as follows. (1) There appears to be a threshold response (clastogenicity vs. dose) with NaF at around 10 micrograms/ml (48 h exposure) but a more definitive conclusion must await elucidation of the mechanisms of clastogenicity. (2) NaCl is weakly clastogenic at 1000 times the threshold dose for NaF. The mechanisms are unlikely to be similar. (3) No clastogenicity was detected with NaF below about 30% mitotic inhibition but the relationship between clastogenicity and mitotic inhibition was similar for NaF and MMC. (4) There was no obvious threshold in the relationship between clastogenicity and cell killing with NaF. MMC was less clastogenic than NaF at equitotoxic doses. Observations 3 and 4 preclude the possibility of regarding the clastogenicity of NaF as a false positive by virtue of associated cytotoxicity.     

Risk estimates for radiation-induced cancer – the epidemiological evidence

The risk of low-dose radiation exposures has – for a variety of reasons – been highly politicised. This has led to a frequently exaggerated perception of the potential health effects, and to lasting public controversies. A balanced view requires a critical reassessment of the epidemiological basis of current assumptions. There is reliable quantitative information available on the increase of cancer rates due to moderate and high doses. This provides a firm basis for the derivation of probabilities of causation, e.g. after high radiation exposures. For small doses or dose rates, the situation is entirely different: potential increases of cancer rates remain hidden below the statistical fluctuations of normal rates, and the molecular mechanisms of cancerogenesis are not sufficiently well known to allow numerical predictions. Risk coefficients for radiation protection must, therefore, be based on the uncertain extrapolation of observations obtained at moderate or high doses. While extrapolation is arbitrary, it is, nevertheless, used and mostly with the conservative assumption of a linear dose dependence with no threshold (LNT model). All risk estimates are based on this hypothesis. They are, thus, virtual guidelines, rather than firm numbers. The observations on the A-bomb survivors are still the major source of information on the health effects of comparatively small radiation doses. A fairly direct inspection of the data shows that the solid cancer mortality data of the A-bomb survivors are equally consistent with linearity in dose and with reduced effectiveness at low doses. In the leukemia data a reduction is strongly indicated. With one notable exception – leukemia after prenatal exposure – these observations are in line with a multitude of observations in groups of persons exposed for medical reasons. The low-dose effects of densely ionizing radiations – such as alpha-particles from radon decay products or high-energy neutrons – are a separate important issue. For neutrons, there is little epidemiological information. This has facilitated exaggerated claims of high neutron effects with reference to alleged dangers from transports of reactor fuel. However, in spite of limited information, it can be shown that the data from Hiroshima exclude the stated claims. New dosimetric information on neutrons may turn out to be highly informative with regard to an upper limit for the potential effects of neutrons and equally with regard to a reassessment – and a possible reduction – of risk estimates for gamma-rays. Received: 13 November 1999 / Accepted in revised form: 13 December 1999     

Ecological Risk Assessment Approaches Within the Regulatory Framework

Ecological risk assessment has a short history but a framework similar to human health risk assessment. The Toxic Substances Control Act (TSCA) and the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) played a significant role in the development of the ecological risk process. Data developed and risk procedures used within TSCA and FIFRA have become generally standardized. Fundamental components of the risk process require data on the effects of chemicals in the form of concentration (or dose) — response profiles for species and an exposure profile to quantify the magnitude, spatial and temporal patterns of exposure relevant to significant biological endpoints being studied. Risk characterization generally involves comparing exposure and effects using point estimates (e.g., quotient method) but risk estimation is moving toward a probabilistic approach by comparing distributions of values with more consideration of the sources of uncertainty. Ecological testing guidelines in TSCA and FIFRA are discussed along with the risk characterization process used in each statute.     

NMR reveals novel mechanisms of protein activity regulation

NMR spectroscopy is one of the most powerful tools for the characterization of biomolecular systems. A unique aspect of NMR is its capacity to provide an integrated insight into both the structure and intrinsic dynamics of biomolecules. In addition, NMR can provide site-resolved information about the conformation entropy of binding, as well as about energetically excited conformational states. Recent advances have enabled the application of NMR for the characterization of supramolecular systems. A summary of mechanisms underpinning protein activity regulation revealed by the application of NMR spectroscopy in a number of biological systems studied in the lab is provided.