Journal of Toxicology & Environmental Health Part A: Current Issues

Lipscomb, John C.; Mattie, David; Dodd, Darol E.

doi: 10.1080/15287390590912144pmid: 16020179

Axelrad, Daniel A.; Baetcke, Karl; Dockins, Chris; Griffiths, Charles W.; Hill, Richard N.; Murphy, Patricia A.; Owens, Nicole; Simon, Nathalie B.; Teuschler, Linda K.

doi: 10.1080/15287390590912153pmid: 16020180

Benefit-cost analysis is of growing importance in developing policies to reduce exposures to environmental contaminants. To quantify health benefits of reduced exposures, economists generally rely on dose-response relationships estimated by risk assessors. Further, to be useful for benefits analysis, the endpoints that are quantified must be expressed as changes in incidence of illnesses or symptoms that are readily understood by and perceptible to the layperson. For most noncancer health effects and for nonlinear carcinogens, risk assessments generally do not provide the dose-response functions necessary for economic benefits analysis. This article presents the framework for a case study that addresses these issues through a combination of toxicology, epidemiology, statistics, and economics. The case study assesses a chemical that disrupts proper functioning of the thyroid gland, and considers the benefits of reducing exposures in terms of both noncancer health effects (hypothyroidism) and thyroid cancers. The effects are presumed to be due to a mode of action involving interference with thyroid–pituitary functioning that would lead to nonlinear dose response. The framework integrates data from animal testing, statistical modeling, human data from the medical and epidemiological literature, and economic methodologies and valuation studies. This interdisciplinary collaboration differs from the more typical approach in which risk assessments and economic analyses are prepared independently of one another. This framework illustrates particular approaches that may be useful for expanded quantification of adverse health effects, and demonstrates the potential of such interdisciplinary approaches. Detailed implementation of the case study framework will be presented in future publications.

Hauschild, Veronique D.; Bratt, Gary M.

doi: 10.1080/15287390590912162pmid: 16020181

This article describes the approach used to develop a prioritized list of toxic and hazardous industrial chemical hazards considered to pose substantial risk to deployed troops and military operations. The U.S. Army Center for Health Promotion and Preventive Medicine published the prioritized list in November 2003. The work was performed as part of a multinational military effort supported by Canada, the United Kingdom, and the United States. Previous chemical priority lists had been developed to support military as well as homeland defense research, development, and acquisition communities to determine enhanced detection and protection needs. However, there were questions as to the adequacy of the methodologies and focus of the previous efforts. This most recent effort is a more extensive evaluation of over 1700 industrial chemicals, with a modified methodology that includes not only the assessment of acute inhalation toxic industrial chemicals (TICs), but also chemicals/compounds that pose substantial physical risk (from fire/explosion) and those that may pose acute ingestion risks (such as in water supplies). The methodology was designed to rank such hazards from a strategic (global) military perspective, but it may be adapted to address more site/user specific needs. Users of this or any other chemical priority list are cautioned that the derivation of such lists is largely influenced by subjective decisions and significant variability in chemical-specific data availability and quality.

Jederberg, Warren W.

doi: 10.1080/15287390590912171pmid: 16020182

In the post-9/11 environment, it has become recognized that the response to man-made disasters (such as chemical spills, bioterrorism, and radiation dispersal) requires a much broader range of tools and technical knowledge than needed for natural disasters (i.e., hurricanes, earthquakes, or drought). This need also requires that those who develop technical information for disaster planning maintain a broader perspective of how the information will be used and what the priorities are for developing new information. In addition, the ability to communicate information within a context understandable to the “end user” has become more critical. The intent of this article is to present issues to help those who traditionally collect and interpret technical information (toxicology, risk assessment, mitigation planners, etc.) to better understand how their information is used in planning for and responding to incidents. These issues are similar to those experienced when trying to provide the users of information provided on material safety data sheets (MSDS) with an understanding of the value and limits of such information in decision making. Confounding the problem are the many sources that provide exposure limits and the limited amount of time the user has to understand the limits of the data during an emergency. While the Federal Response Plan integrates the efforts of multiple agencies, the “on-scene” responders are faced with trying to respond to contradictory strategies and applications of information. Sources of response technical information need to better communicate the limits of application/interpretation of that information in emergency situations.

Barton, Hugh A.

doi: 10.1080/15287390590912180pmid: 16020183

Computational modeling has an increasing role in analyses of biological effects, including how the body handles chemicals (i.e., pharmacokinetics or toxicokinetics) and how the body responds to chemicals (i.e., pharmacodynamics or toxicodynamics). Pharmacokinetic models increasingly describe not just adult humans and animals, but also changes with age and life stage (e.g., pregnancy and fetal exposures, lactational exposures, and childhood growth). Physiologically based pharmacokinetic models provide an important route to estimate the potential changes in internal dose that may occur throughout the life cycle. These models require inputs describing changes in physiology, metabolism, and exposure with age and life stage. A particular challenge exists when the “equivalent” developmental period in the rodents and humans differs (e.g., early postnatal in rats and in utero in humans) such that the “equivalent” window of susceptibility to toxic effects of the chemical may involve substantially different exposures (e.g., lactational versus placental transfer). Pharmacodynamic modeling could similarly address changes with age, but few such models currently exist. The growth of systems biology is anticipated to change this over the coming decade.

Woodall, George M.

doi: 10.1080/15287390590912199pmid: 16020184

A number of organizations have developed acute inhalation health reference values, each with (1) a specific purpose, (2) populations to protect, (3) exposure scenarios (accidental releases, workplace, routine excursions of ambient levels), and (4) severity of adverse health effects considered in their development. The first section of this article reviews the existing values from different organizations and describes their purposes and method of development. The second part of the article provides a comparative review of how the values were derived, the critical endpoints considered for each value, the populations being protected by each value, and the potential for use outside of their intended purpose (e.g., Homeland Security, regulatory analysis, etc.). Additionally, an analysis of the acute inhalation reference values that was developed in support of the Office of Air and Radiation's residual risk assessment for hazardous air pollutants is presented and reviewed. The third and final part of the article focuses on the efforts of the U.S. Environmental Protection Agency (EPA) to develop a set of less-than-lifetime reference values, along with a discussion of how that effort fits with the existing sets of values described in the prior sections.

Simmons, Jane Ellen; Evans, Marina V.; Boyes, William K.

doi: 10.1080/15287390590912586pmid: 16020185

The potential human health risk(s) from chemical exposure must frequently be assessed under conditions for which adequate human or animal data are not available. The default method for exposure-duration adjustment, based on Haber's rule, C (external exposure concentration) or C n (the ten Berge modification) × t (exposure duration) = K (a constant toxic effect), has been criticized for prediction errors. A promising alternative approach to duration adjustment is based on equivalence of internal dose, that is, target-tissue dose levels, across different exposure durations. A proposed methodology for dose-duration adjustments for acute exposure guideline levels (AEGLs) based on physiologically based pharmacokinetic (PBPK) estimates of dose is illustrated with trichloroethylene (TCE). Steps in this methodology include: (1) selection and evaluation, or development and evaluation, of an appropriate PBPK model; (2) determination of an appropriate measure of internal dose; (3) estimation with the PBPK model of the tissue dose (the target tissue dose) resulting from the external exposure conditions (concentration, duration) of the critical effect; (4) estimation of the external exposure concentrations required to achieve tissue doses equivalent to the target tissue dose at exposure durations of interest; and (5) evaluation of sources of variability and uncertainty. For TCE, this PBPK modeling approach has allowed determination of dose metrics predictive of the acute neurotoxic effects of TCE and dose-duration adjustments based on estimates of internal dose.

Mitchell, Sarah E.; Caldwell, Colleen A.; Gonzales, Gil; Gould, William R.; Arimoto, Richard

doi: 10.1080/15287390590912595pmid: 16020186

Embryos (stage 8–47, Nieuwkoop and Faber) of the African clawed frog (Xenopus laevis) were subjected to water-borne depleted uranium (DU) concentrations that ranged from 4.8 to 77.7 mg/L using an acute 96-h frog embryo teratogenesis assay–Xenopus (FETAX). In a chronic 64-d assay, X. laevis (from embryo through metamorphosis; stages 8–66) were subjected to concentrations of DU that ranged from 6.2 to 54.3 mg/L. Our results indicate DU is a non teratogenic metal. No effects on mortality, malformations, or growth were observed in the 96-h FETAX with concentrations of DU that ranged from 4.8 to 77.7 mg/L. From stage 8 to stage 47, X. laevis tadpoles do not actively feed and the gills are not well developed. Thus, uptake of DU was reduced despite exposure to elevated concentrations. The 64-d assay resulted in no concentration response for either mortality or malformations; however, a delay in metamorphosis was observed in tadpoles subjected to elevated DU concentrations (from 13.1 to 54.3 mg/L) compared to tadpoles in both the well-water control and reference. The delay in metamorphosis was likely due to increasing body burden of DU that ranged from 0.98 to 2.82 mg/kg.

Arfsten, D. P.; Bekkedal, M.; Wilfong, E. R.; Rossi III, J.; Grasman, K. A.; Healey, L. B.; Rutkiewicz, J. M.; Johnson, E. W.; Thitoff, A. R.; Jung, A. E.; Lohrke, S. R.; Schaeffer, D. J.; Still, K. R.

Hubbs, Ann; Greskevitch, Mark; Kuempel, Eileen; Suarez, Fernando; Toraason, Mark

doi: 10.1080/15287390590912612pmid: 16020188

Workers exposed to respirable crystalline silica used in abrasive blasting are at increased risk of developing a debilitating and often fatal fibrotic lung disease called silicosis. The National Institute for Occupational Safety and Health (NIOSH) recommends that silica sand be prohibited as abrasive blasting material and that less hazardous materials be used in blasting operations. However, data are needed on the relative risks associated with exposure to abrasive blasting materials other than silica. NIOSH has completed acute studies in rats (Hubbs et al., 2001; Porter et al., 2002). To provide dose-response data applicable to making recommendation for occupational exposure limits, NIOSH has collaborated with the National Toxicology Program (NTP) to design longer term studies with silica substitutes. For risk assessment purposes, selected doses will include concentrations that are relevant to human exposures. Rat lung burdens achieved should be comparable to those estimated in humans with working lifetime exposures, even if this results in “overloading” doses in rats. To quantify both dose and response, retained particle burdens in the lungs and lung-associated lymph nodes will be measured, as well as biochemical and pathological indices of pulmonary response. This design will facilitate assessment of the pulmonary fibrogenic potential of inhaled abrasive blasting agents at occupationally relevant concentrations.