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.     

The Use of Epidemiology in Environmental Risk Assessment

Epidemiology provides estimates of the concentration–response relation for environmental and occupational toxicants in the species of interest, in or close to the dose range of interest. As such, when available, they provide the primary source for risk assessments. Further information can be acquired by using modern biostatistical techniques to assess the shape of the dose response relation, examine effect modification, and assure control for confounding. These approaches are particularly effective if they are done in the context of a meta-analysis or hierarchical model. This is illustrated with examples from the air pollution literature.     

Ecological Risk Assessment of Radiological Exposure to Depleted Uranium in Soils at a Weapons Testing Facility

The potential for unacceptable risks to biota from radiological exposure to depleted uranium (DU) in soils was evaluated at two sites where DU weapons testing had been conducted in the past. A screening risk assessment was conducted to determine if measured concentrations of DU-associated radionuclides in site soils exceed radionuclide levels considered protective of biota. While concentrations of individual radionuclides did not exceed acceptable levels, total radionuclide concentrations could result in potentially unacceptable doses to exposed biota. Thus, a receptor-specific assessment was conducted to estimate external and internal radiological doses to vegetation and wildlife known or expected to occur at the sites. Wildlife evaluated included herbivores, omnivores, and top-level predators. Internal dose estimates to wildlife considered exposure via fugitive dust inhalation and soil and food ingestion; root uptake was the primary exposure route evaluated for vegetation. Total doses were compared with acceptable dose levels of 1.0 and 0.1 rad/day for vegetation and wildlife, respectively, with potentially unacceptable risks indicated for doses exceeding these levels. All estimated doses were below or approximated acceptable levels, typically by an order of magnitude or more. These results indicate that current levels of DU in soils do not pose unacceptable radiological risks to biota at the sites evaluated.     

Use of meta‐analysis to predict degradation of carbaryl and malathion in freshwater for exposure assessment

Carbaryl (1‐naphthyl methylcarbamate) and malathion (diethyl mercaptosuccinate, S‐ester with O, O‐dimethyl phosphorodithioate) are insecticides used to control grasshopper infestations on rangeland. Insecticides used to control grasshopper infestations pose a hazard to aquatic organisms because although no‐spray buffer zones are observed around aquatic habitats, pesticide may be deposited by drift or mobilized from upland areas by runoff. A number of processes may affect the fate of carbaryl and malathion in the aquatic environment, but no method is available for estimating degradation over the range of conditions that occur in the field. We used results of published studies in meta‐analyses to estimate degradation models that predict half‐life of carbaryl and malathion in freshwater over temperature and pH ranges relevant to western grasshopper‐management programs. Estimated degradation models were:

In (half‐life carbaryl) = 24.3 ‐ 2.36(pH) ‐ 0.0788(t)

and In (half‐life malathion) = 5.98 + 2.84(pH) ‐ 0.326(pH ²) ‐ 0.202(t) + 0.00135(t ²)

where half‐life has units of hours, and temperature (t) has units °C. Both models accounted for a significant amount of total variation (P<0.0001) and had r²>0.97. Accuracy of these degradation models was evaluated by comparing predicted degradation of carbaryl and malathion to field and laboratory data. We suggest that use of these degradation models be restricted to conditions where water has 7 ≤. pH ≤. 10 for carbaryl, and 7 ≤ pH ≤ 8.2 for malathion.     

Conceptual Site Models and Multimedia Modeling: Comparing MEPAS,MMSOILS, and RESRAD

The use of multimedia models to assess current and future human and ecological exposure to contamination at hazardous waste sites has become common practice in recent years. The U.S. Environmental Protection Agency has identified development of a conceptual site model as a critical part of the risk assessment process. This paper investigates the relationship between the choice of conceptual site models and application of multimedia models and the variation in risk estimates obtained when using data and default parameter values suggested by the individual model developers.     

Comparison Between Radiological and Chemical Health Risks Assessments: The Nord-Cotentin Study

In 1997, the French Ministries of the Environment and Health commissioned a detailed radioecological analysis of the Nord-Cotentin region in response to public concern about radiological risks associated with local nuclear facilities. This work was entrusted to the Groupe Radioécologie Nord-Cotentin (GRNC), a working group of experts from various origins (industrial facilities operators, public institutions, monitoring agencies, public interest and citizens groups, foreign experts). An epidemiology investigation in 1995 had reported an excess of two radiation-induced leukemia cases in an area near a nuclear reprocessing plant, a finding that attracted great interest in France, and which stimulated the need for further investigation. After the publication of its report in 1999, the GRNC was again commissioned to perform, inter alia, a corresponding assessment on the chemical releases of the local nuclear facilities. This second stage is now achieved and has revealed important similarities as well as some important differences between radiological and chemical risk assessments when applied to the specific case of the Nord-Cotentin nuclear facilities. Due to the considerable amount of work and results of the GRNC, the purpose for this article is to briefly describe the main developments of the risk assessment methodology followed by the GRNC in both cases, to detail some of the main results and to identify and explain, at each step, the similarities and the differences. The whole technical documents that support these works are available on the Internet at ?http://www.irsn.fr/nord-cotentin/?.     

Harmonization: Developing Consistent Guidelines for Applying Mode of Action and Dosimetry Information to Cancer and Noncancer Risk Assessment

The 1983 book, Risk Assessment in the Federal Government: Managing the Process, recommended developing consistent inference guidelines for cancer risk assessment. Over the last 15 years, extensive guidance have been provided for hazard assessment for cancer and other endpoints. However, as noted in several recent reports, much less progress has occurred in developing consistent guidelines for quantitative dose response assessment methodologies. This paper proposes an approach for dose response assessment guided by consideration of mode of action (pharmacodynamics) and tissue dosimetry (pharmacokinetics). As articulated here, this systematic process involves eight steps in which available information is integrated, leading first to quantitative analyses of dose response behaviors in the test species followed by quantitative analyses of relevant human exposures. The process should be equally appropriate for both cancer and noncancer endpoints. The eight steps describe the necessary procedures for incorporating mechanistic data and provide multiple options based upon the mode of action by which the chemical causes the toxicity. Given the range of issues involved in developing such a procedure, we have simply sketched the process, focusing on major approaches for using toxicological data and on major options; many details remain to be filled in. However, consistent with the revised carcinogen risk assessment guidance (USEPA, 1996c), we propose a process that would ultimately utilize biologically based or chemical specific pharmacokinetic and pharmacodynamic models as the backbone of these analyses. In the nearer term, these approaches will be combined with analysis of data using more empirical models including options intended for use in the absence of detailed information. A major emphasis in developing any harmonized process is distinguishing policy decisions from those decisions that are affected by the quality and quantity of toxicological data. Identification of data limitations also identifies areas where further study should reduce uncertainty in the final risk evaluations. A flexible dose response assessment procedure is needed to insure that sound toxicological study results are appropriately used to influence risk management decision-making and to encourage the conduct of toxicological studies oriented toward application for dose response assessments.     

On the Definition of Internal Dose Metrics

Internal dose metrics, as computed with pharmacokinetic models, are increasingly used as a means for extrapolating animal toxicological data to humans and to extrapolate across routes of administration. These internal dose metrics are thought to provide a more scientific means of comparing toxicological effects across animal species. The use of internal dose metrics is based on the universal assumption that toxic effects are equal across species if and only if the concentration of the toxic moieties in the target tissue is equal across species. Herein it is shown that this assumption is inconsistent with empirical toxicological data. It is shown that measurement of internal dose metrics in chronological time, as is done for AUC (Area under the concentration curve) and rate of metabolite production per kg of target tissue, does not produce equal toxic effects across species. A consequence of this observation is that the application of pharmacokinetics in risk assessments for such important chemicals as trichloroethylene, vinyl chloride, perchloroethylene, and perchlorate may need reassessment.     

What Can Be Done to Ensure the Usefulness of Epidemiologic Data for Risk Assessment Purposes?

Epidemiologic studies can play a central role in risk assessments. They are used in all risk assessment phases: hazard identification, dose-response, and exposure assessment. Epidemiologic studies have often been the first to show that a particular environmental exposure is a hazard to health. They have numerous advantages with respect to other sources of data which are used in risk assessments, the most important being that they do not require the assumption that they are generalizable to humans. For this reason, fewer and lower uncertainty factors may be appropriate in risk characterization based on epidemiologic studies. Unfortunately, epidemiologic studies have numerous problems, the most important being that the exposures are often not precisely measured. This article presents in detail the advantages of and problems with epidemiologic studies. It discusses two approaches to ensure their usefulness, biomarkers and an ordinance which requires baseline and subsequent surveillance of possible exposures and health effects from newly sited potentially polluting facilities. Biomarkers are biochemical measures of exposure, susceptibility factors, or preclinical pathological changes. Biomarkers are a way of dealing with the problems of poor measures, differential susceptibility and lack of early measures of disease occurrence that inherent in many environmental epidemiologic studies. The advantages of biomarkers is they can provide objective information on exposure days, months or even years later and evidence of pathology perhaps years earlier. The ordinance makes possible the use of a powerful epidemiologic study design, the prospective cohort study, where confounder(s) are best measured, and exposures, pathological changes, and health effects can be detected as soon as possible.     

Biologically Based Prediction of Empirical Nonlinearity in Lung Cancer Risk vs. Residential/ Occupational Radon Exposure

Ecologic U.S. county data suggest negative associations between residential radon exposure and lung cancer mortality (LCM) that are inconsistent with clearly positive ones revealed by individual data on underground miners. If this inconsistency is due to competing effects of induced cell killing vs. mutations in alpha-radiation exposed bronchial epithelium, then linear extrapolation from miner data may overestimate typical residential radon risks. To investigate the plausibility of this hypothesis, a biologically based “cytodynamic 2-stage” (CD2) cancer-risk model was fit to combined 1950 to 1954 age-specific person-year data on white females of age 40+ y in 2821 U.S. counties (～90% never-smokers), and on five cohorts of underground miners who never smoked, conditional on a realistic rate of alpha-radiation-induced killing of human lung cells, and on linear-no-threshold dose-response relations for both processes assumed to affect cancer risk (alpha-induced mutations and cell killing). As summarized previously (Bogen, K.T., Hum. Exper. Toxicol. 17:691-6, 1998), a good CD2 fit was obtained that involved biologically plausible parameter values and (without further optimization) also predicted inverse dose-rate effects observed in the nonsmoking miners. The present paper reports mathematical details of the CD2 model used, as well as additional modeling results involving the same combined data set. The results obtained are consistent with the hypotheses that low-level radon exposure is nonlinearly related to LCM risk, and that current linear no-threshold extrapolation models overestimate LCM risk associated with relatively low residential radon concentrations (<～200?Bq m^?3). Testing this hypothesis would require more extensive individual-level epidemiological data relating residential radon exposures to LCM than are currently available.     

Effects of Metal Mixtures on Aquatic Biota: A Review of Observations and Methods

A brief review of the historical development of metal mixture interaction analyses is presented. The two major classifications of mixture models are outlined, the “Concentration Addition” and the “Response Addition” approaches. Within these two categories, a number of graphical, mathematical and statistical methods have been used, such as the toxic unit approach, relative potencies, toxicity equivalence factors, and dose-response relationships that have been described using several methods such as probit, logit, and regression analyses. A database was generated to evaluate the frequency of occurrence of less than additive, strictly additive, and more than additive responses to metal mixture effects reported in the literature. The three responses occurred at 43, 27, and 29%, respectively. The database is available electronically from the lead author. The research required to determine the most appropriate methods to quantify the effects of metal mixtures in an ecological risk assessment (ERA) framework is discussed. Until this research is completed, ERAs should use existing models such as the toxic unit or the effects addition approach. Bioaccumulation measurements by organisms for which the accumulation to response relationship is known would also be a useful complement.     

Imprecise exposure assessment and the sample size requirements of case-control studies of residential magnetic field exposure and cancer in adults

A computer program simulating case-control studies is described. It is used to estimate the minimum sample size required and to assess how this is affected by imprecise exposure assessment. In particular, the consequences of neglecting measurements of nonresidential exposure in case-control studies of residentially exposed adults are investigated. According to this model, while the consequent loss of power is not as large as was predicted by algebraic methods, it would be unwise to neglect it when planning a study. © 1995 Wiley-Liss, Inc.     

Estimates of real damage from air pollution: Site dependence and simple impact indices for LCA

In contrast to the various “potential impact” indices that have been proposed, we show that indices for real damage can be derived, based on the impact pathway methodology which involves the calculation of increased pollutant concentration in all affected regions due to an incremental emission (e.g. μg/m³ of particles, using models of atmospheric dispersion and chemistry), followed by the calculation of physical impacts (e.g. number of cases of asthma due to these particles, using a concentration-response function). The numbers are summed over all receptors of concern (population, crops, buildings,…). We show that in a uniform world (linear dose-response function, uniform receptor density and uniform atmospheric removal rate) the conservation of matter implies a very simple formula for the total damage. The generalization to secondary pollutants is straightforward. By detailed numerical evaluations, using real data for atmospheric dispersion and geographic receptor distribution, we have demonstrated that this simple formula is an excellent representation of typical damages. Results are shown for the principal air pollutants emitted by smoke stacks of industrial installations or by road transport. A preliminary version was presented as a key note lecture at the SETAC Meeting in Bordeaux, April 14-18, 1998     

Quantitative Exposure-Response Assessment Approaches to Evaluate Acute Inhalation Toxicity of Phosgene

Phosgene has been a long-term subject of toxicological research due to its widespread use, high toxicity, and status as a model of chemically induced lung injury. To take advantage of the abundant data set for the acute inhalation toxicity of phosgene, methods for exposure-response analysis that use more data than the traditional no-observed-adverse-effect level approach were used to perform an exposure-response assessment for phosgene. Categorical regression is particularly useful for acute exposures due to the ability to combine studies of various exposure durations, and thus provide estimates of effect severity for a range of both exposure concentrations and durations. Results from the categorical regression approach were compared to those from parametric curve fitting models (i.e., benchmark concentration models) that make use of information from an entire dose-response, but only for one exposure duration. While categorical regression analysis provided results that were comparable to benchmark concentration results, categorical regression provides an improvement over that technique by accounting for the effects of both exposure concentration and duration on response. The other major advantage afforded by categorical regression is the ability to combine studies, allowing the quantitative use of a larger data set, which increases confidence in the final result.