Issues in Exposure and Dose Assessment for Epidemiology and Risk Assessment

Epidemiologic studies have been effective in identifying human environmental and occupational hazards. However, most epidemiologic data has been difficult to use in quantitative risk assessments because of the vague specification of exposure and dose. Toxicologic animal studies have used applied doses (quantities administered, or exposures with fixed duration) and well characterized end points to determine effects. However, direct use of animal data in human risk assessment has been limited by uncertainties in the extrapolation. The applied dose paradigm of toxicology is not suited for cross species extrapolation, nor for use in epidemiology as a dose metric because of the complexity of human exposures. Physiologically based pharmacokinetic (PBPK) modeling can estimate the time course of tissue concentrations in humans, given an exposure-time profile, and it has been used for extrapolating findings from animals to humans. It is proposed that human PBPK modeling can be used in appropriately designed epidemiologic studies to estimate tissue concentrations. Secondly, tissue time courses can be used to form dose metrics based on the type and time course of adverse effects. These dose metrics will strengthen the determination of epidemiologic dose-response relationships by reducing misclassification. Findings from this approach can be readily integrated into quantitative risk assessment.     

An Assessment of Integrated Risk Assessment

In order to promote international understanding and acceptance of the integrated risk assessment process, the World Health Organization/International Programme on Chemical Safety (WHO/IPCS), in collaboration with the U.S. Environmental Protection Agency and the Organization for Economic Cooperation and Development, initiated a number of activities related to integrated risk assessment. In this project, the WHO/IPCS defines integrated risk assessment as a science-based approach that combines the processes of risk estimation for humans, biota, and natural resources in one assessment. This article explores the strengths and weaknesses of integration as identified up to this date and the degree of acceptance of this concept by the global risk assessment/risk management community. It discusses both opportunities and impediments for further development and implementation.

The major emerging opportunities for an integrated approach stem from the increasing societal and political pressure to move away from vertebrate testing leading to a demand for scientific integrated approaches to in vitro and in vivo testing, as well as to computer simulations, in so-called Intelligent Testing Strategies. In addition, by weighing the evidence from conventional mammalian toxicology, ecotoxicology, human epidemiology, and eco-epidemiology, risk assessors could better characterize mechanisms of action and the forms of the relationships of exposures to responses. It is concluded that further demonstrations of scientific, economic and regulatory benefits of an integrated approach are needed. As risk assessment is becoming more mechanistic and molecular this may create an integrated approach based on common mechanisms and a common systems-biology approach.     

Using Ecological Risk Assessment Principles in a Source Water Protection Assessment

It has become increasingly common to apply ecological risk assessment (ERA) principles to watershed and regional scale environmental management. This article describes the application of watershed ERA principles to the development of a source water protection assessment and a strategic watershed management plan. The primary focus was on the protection of drinking water quality, a concern typically addressed by human health risk assessors. The approach emphasizes adaptations to the problem formulation phase of ERA (defining assessment endpoints, developing conceptual models and an analysis plan) suitable for watershed management planning in a multi-objective, multi-stressor context. Physical, chemical, and biological attributes were selected for primary drinking water quality assessment endpoints, and coupled with additional assessment endpoints relevant to other environmental and social management objectives. Conceptual models helped the planning team to better understand and communicate the multiple natural and human stressors in the watershed and the causal pathways by which they affected drinking water. The article provides an example of the types of adaptations that can make ERA principles suitable for watershed management related to human health goals, and illustrates the efficiency of integrating health and ecological assessments.     

Swimming Performance Assessment in Fishes

Swimming performance tests of fish have been integral to studies of muscle energetics, swimming mechanics, gas exchange, cardiac physiology, disease, pollution, hypoxia and temperature. This paper describes a flexible protocol to assess fish swimming performance using equipment in which water velocity can be controlled. The protocol involves one to several stepped increases in flow speed that are intended to cause fish to fatigue. Step speeds and their duration can be set to capture swimming abilities of different physiological and ecological relevance. Most frequently step size is set to determine critical swimming velocity (U_crit), which is intended to capture maximum sustained swimming ability. Traditionally this test has consisted of approximately ten steps each of 20 min duration. However, steps of shorter duration (e.g. 1 min) are increasingly being utilized to capture acceleration ability or burst swimming performance. Regardless of step size, swimming tests can be repeated over time to gauge individual variation and recovery ability. Endpoints related to swimming such as measures of metabolic rate, fin use, ventilation rate, and of behavior, such as the distance between schooling fish, are often included before, during and after swimming tests. Given the diversity of fish species, the number of unexplored research questions, and the importance of many species to global ecology and economic health, studies of fish swimming performance will remain popular and invaluable for the foreseeable future.     

Cognitive Processes in Odorant Mixture Assessment

‘Comparison of models of odor interaction’ by Cainand his colleagues (1995) is a turning point in assessment ofthe strengths of smell of mixtures of odorants. Their paperprovides the best empirical comparison to date of models of(olfactory) binary mixture intensities and combines this analysiswith a cogent critique of the whole tradition of mixture psychophysics.This commentary on their paper argues that their critique isnot radical enough. Chem. Senses 20: 639–643, 1995.     

Economic Allocation in Life Cycle Assessment

This article examines methods for analyzing allocation in life cycle assessment (LCA); it focuses on comparisons of economic allocation with other feasible alternatives. The International Organization for Standardization's (ISO) guideline 14044 indicates that economic allocation should only be used as a last resort, when other methods are not suitable. However, the LCA literature reports several examples of the use of economic allocation. This is due partly to its simplicity and partly to its ability to illustrate the properties of complex systems. Sometimes a price summarizes complex attributes of product or service quality that cannot be easily measured by physical criteria. On the other hand, economic allocation does have limitations arising, for example, from the variability of prices and the low correlation between prices and physical flows. This article presents the state of the debate on the topic and some hypothetical examples for illustration. A general conclusion is that it is not possible to determine one “best” allocation method. The allocation procedure has to be selected on a case‐by‐case basis and no single approach is suitable for every situation. Despite its limitations, economic allocation has certain qualities that make it flexible and potentially suitable for different contexts. In some situations, economic allocation should not be the last methodological resort. The option of economic allocation should be considered, for example, whenever the prices of coproducts and coservices differ widely.     

Nerve Excitability Assessment in Chemotherapy-induced Neurotoxicity

Chemotherapy-induced neurotoxicity is a serious consequence of cancer treatment, which occurs with some of the most commonly used chemotherapies^1,2. Chemotherapy-induced peripheral neuropathy produces symptoms of numbness and paraesthesia in the limbs and may progress to difficulties with fine motor skills and walking, leading to functional impairment. In addition to producing troubling symptoms, chemotherapy-induced neuropathy may limit treatment success leading to dose reduction or early cessation of treatment. Neuropathic symptoms may persist long-term, leaving permanent nerve damage in patients with an otherwise good prognosis³. As chemotherapy is utilised more often as a preventative measure, and survival rates increase, the importance of long-lasting and significant neurotoxicity will increase.There are no established neuroprotective or treatment options and a lack of sensitive assessment methods. Appropriate assessment of neurotoxicity will be critical as a prognostic factor and as suitable endpoints for future trials of neuroprotective agents. Current methods to assess the severity of chemotherapy-induced neuropathy utilise clinician-based grading scales which have been demonstrated to lack sensitivity to change and inter-observer objectivity⁴. Conventional nerve conduction studies provide information about compound action potential amplitude and conduction velocity, which are relatively non-specific measures and do not provide insight into ion channel function or resting membrane potential. Accordingly, prior studies have demonstrated that conventional nerve conduction studies are not sensitive to early change in chemotherapy-induced neurotoxicity^4-6. In comparison, nerve excitability studies utilize threshold tracking techniques which have been developed to enable assessment of ion channels, pumps and exchangers in vivo in large myelinated human axons^7-9.Nerve excitability techniques have been established as a tool to examine the development and severity of chemotherapy-induced neurotoxicity^10-13. Comprising a number of excitability parameters, nerve excitability studies can be used to assess acute neurotoxicity arising immediately following infusion and the development of chronic, cumulative neurotoxicity. Nerve excitability techniques are feasible in the clinical setting, with each test requiring only 5 -10 minutes to complete. Nerve excitability equipment is readily commercially available, and a portable system has been devised so that patients can be tested in situ in the infusion centre setting. In addition, these techniques can be adapted for use in multiple chemotherapies.In patients treated with the chemotherapy oxaliplatin, primarily utilised for colorectal cancer, nerve excitability techniques provide a method to identify patients at-risk for neurotoxicity prior to the onset of chronic neuropathy. Nerve excitability studies have revealed the development of an acute Na⁺ channelopathy in motor and sensory axons^10-13. Importantly, patients who demonstrated changes in excitability in early treatment were subsequently more likely to develop moderate to severe neurotoxicity¹¹. However, across treatment, striking longitudinal changes were identified only in sensory axons which were able to predict clinical neurological outcome in 80% of patients¹⁰. These changes demonstrated a different pattern to those seen acutely following oxaliplatin infusion, and most likely reflect the development of significant axonal damage and membrane potential change in sensory nerves which develops longitudinally during oxaliplatin treatment¹⁰. Significant abnormalities developed during early treatment, prior to any reduction in conventional measures of nerve function, suggesting that excitability parameters may provide a sensitive biomarker.     

Axes of Extrapolation in Risk Assessment

Extrapolation in risk assessment involves the use of data and information to estimate or predict something that has not been measured or observed. Reasons for extrapolation include that the number of combinations of environmental stressors and possible receptors is too large to characterize risks comprehensively, that direct characterization is sometimes impossible, and that the power to characterize risk in a particular situation can be enhanced by using information obtained in other similar situations. Three types of extrapolation are common in risk assessments: biological (including between taxa and across levels of biological organization), temporal, and spatial. They can be thought of conceptually as the axes of a 3-dimensional graph defining the state space of biological, temporal, and spatial scales within which extrapolations are made. Each of these types of extrapolation can introduce uncertainties into risk assessments. Such uncertainties may be reduced through synergistic research facilitated by the sharing of methods, models, and data used by human health and ecological scientists     

Life-Cycle Assessment in the Service Industries

Despite the dominant role service industries play in modern society, those industries have by and large not been involved in the strong efforts underway to create environmentally responsible operations. Part of the reason is that the role of these industries as driving factors in resource flows has not been recognized. Perhaps more important, no common framework for assessing the environmental responsibility of service industries has been established. This article provides such a framework and applies it to a generic service industry: automotive repair. Among the results are that evaluation must take different forms for different types of services, and that the approaches of service industries to the use of buildings and equipment will require innovative solutions quite unlike those advocated for the "greening" of manufacturing operations.     

Biohazards Assessment in Large-Scale Zonal Centrifugation

A study was conducted to determine the biohazards associated with use of the large-scale zonal centrifuge for purification of moderate risk oncogenic viruses. To safely and conveniently assess the hazard, coliphage T₃ was substituted for the virus in a typical processing procedure performed in a National Cancer Institute contract laboratory. Risk of personnel exposure was found to be minimal during optimal operation but definite potential for virus release from a number of centrifuge components during mechanical malfunction was shown by assay of surface, liquid, and air samples collected during the processing. High concentration of phage was detected in the turbine air exhaust and the seal coolant system when faulty seals were employed. The simulant virus was also found on both centrifuge chamber interior and rotor surfaces.     

Assessment of physical activity in youth

Despite much progress with physical activity assessment, the limitations concerning the accurate measurement of physical activity are often amplified in young people due to the cognitive, physiological, and biomechanical changes that occur during natural growth as well as a more intermittent pattern of habitual physical activity in youth compared with adults. This mini-review describes and compares methods to assess habitual physical activity in youth and discusses main issues regarding the use and interpretation of data collected with these techniques. Self-report instruments and movement sensing are currently the most frequently used methods for the assessment of physical activity in epidemiological research; others include heart rate monitoring and multisensor systems. Habitual energy expenditure can be estimated from these input measures with varying degree of uncertainty. Nonlinear modeling techniques, using accelerometry perhaps in combination with physiological parameters like heart rate or temperature, have the greatest potential for increasing the prediction accuracy of habitual physical activity energy expenditure. Although multisensor systems may be more accurate, this must be balanced against feasibility, a balance that shifts with technological and scientific advances and should be considered at the beginning of every new study.     

Assessment of hyphal binding in tempe

An inverse three-point bending test method is described for measuring the strength of the hyphae binding the cotyledons together in soybean tempe. The force to failure and the work to failure both increased from zero values before hyphal development to maximum values after about 30 h incubation and then declined as the tempe aged and hyphae started to senesce. The changes in force to failure and work to failure closely paralleled changes in the appearance and manual assessments of the texture of the tempes.