Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels.

Provisional Advisory Levels (PALs) are tiered exposure limits for toxic chemicals in air and drinking water that are developed to assist in emergency responses. Physiologically-based pharmacokinetic (PBPK) modeling can support this process by enabling extrapolations across doses, and exposure routes, thereby addressing gaps in the available toxicity data. Here, we describe the development of a PBPK model for Fentanyl - a synthetic opioid used clinically for pain management - to support the establishment of PALs. Starting from an existing model for intravenous Fentanyl, we first optimized distribution and clearance parameters using several additional IV datasets. We then calibrated the model using pharmacokinetic data for various formulations, and determined the absorbed fraction, F, and time taken for the absorbed amount to reach 90% of its final value, t90. For aerosolized pulmonary Fentanyl, F=1 and t90<1 min indicating complete and rapid absorption. The F value ranged from 0.35 to 0.74 for oral and various transmucosal routes. Oral Fentanyl was absorbed the slowest (t90~300 min); the absorption of intranasal Fentanyl was relatively rapid (t90~20-40 min); and the various oral transmucosal routes had intermediate absorption rates (t90~160-300 min). Based on these results, for inhalation exposures, we assumed that all of the Fentanyl inhaled from the air during each breath directly, and instantaneously enters the arterial circulation. We present model predictions of Fentanyl blood concentrations in oral and inhalation scenarios relevant for PAL development, and provide an analytical expression that can be used to extrapolate between oral and inhalation routes for the derivation of PALs.

Overview of the Standing Operating Procedure (SOP) for the development of Provisional Advisory Levels (PALs).

Provisional Advisory Levels (PALs) are concentrations in air and drinking water for priority toxic chemicals. This article summarizes the Standing Operating Procedure (SOP) currently in place for the data-driven development of chemical-specific PALs. To provide consistency and transparency, and to avoid faults of arbitrariness, the SOP was developed for guidance in deriving PAL values. Three levels (PAL 1, PAL 2, and PAL 3), distinguished by severity of toxic effects, are developed for 24-hour, 30-day, 90-day, and 2-year durations of potential drinking water and inhalation exposures for the general public. The SOP for PAL development focuses on (1) data acquisition and analysis, (2) identification of a chemical-specific critical effect, (3) selection of a quantitative point-of-departure (POD), (4) uncertainty analysis and adjustments, (5) exposure duration adjustment and extrapolation, (6) identification of special concerns and issues, and (7) verification, documentation, and dissemination of PALs. To avoid uncompromising rigidity in deriving PAL values and to allow for incorporation of new or refined methodologies, the overall procedure is fluid and subject to modification. The purpose of this publication is to provide a summary of this SOP.

Provisional Advisory Levels (PALs) for acrylonitrile.

Application of Provisional Advisory Level (PAL) protocols was performed for acrylonitrile, as experimental data permitted. Three levels (PAL 1, PAL 2, and PAL 3), distinguished by severity of toxic effects, are developed for 24-hour, 30-day, 90-day, and 2-year durations of potential drinking water and inhalation exposures for the general public. For background on the PAL Program and a description of the methodology used in deriving PALs, the reader is referred to accompanying papers in this Supplement. Human data were limited to inhalation exposures. The animal experimental data set for this chemical was robust for inhalation and oral studies, with the exception of appropriate data for inhalation 30-day, 90-day, and 2-year PAL 3 values. PAL estimates were approved by the Expert Consultation Panel for Provisional Advisory Levels in October 2007. Oral 24-hour PALs for acrylonitrile are PAL 1 = 7 mg/L; PAL 2 = 23 mg/L; and PAL 3 = 88 mg/L. Oral 30-day and 90-day PALs are PAL 1 = 0.35 mg/L; PAL 2 = 7 mg/L; and PAL 3 = 17 mg/L. Oral 2-year PALs are PAL 1 = 0.35 mg/L; PAL 2 = 3.5 mg/L; and PAL 3 = 12 mg/L. Acrylonitrile inhalation PAL values for 24-hour exposure are PAL 1 = 0.17 ppm; PAL 2 = 3.5 ppm; and PAL 3 = 5.1 ppm; the 30-day and 90-day inhalation exposure values are PAL 1 = 0.15 ppm and PAL 2 = 0.60 ppm. The 2-year inhalation values are PAL 1 = 0.014 ppm and PAL 2 = 0.12 ppm. PAL 3 values for 30 days, 90 days, and 2 years are not recommended due to insufficient data.

Provisional Advisory Levels (PALs) for hydrogen sulfide (H2S).

Application of Provisional Advisory Levels (PALs) protocols was performed for hydrogen sulfide (H(2)S) as experimental data permitted. Three levels (PAL 1, PAL 2, and PAL 3), distinguished by severity of toxic effects, are developed for 24-hour, 30-day, 90-day, and 2-year durations of potential drinking water and inhalation exposures for the general public. For background on the PAL program and a description of the methodology used in deriving PALs, the reader is referred to accompanying papers in this Supplement. The database includes human experimental studies, worker exposure evaluations, as well as case studies on acute and repeated exposure. The database of animal studies is substantial, covering multiple species and addressing acute, repeated, and subchronic exposure scenarios. PAL estimates were approved by the Expert Consultation Panel for Provisional Advisory Levels in November 2006. No reliable data were found on oral exposure, making it impractical to estimate PALs for drinking water. Because H(2)S exists as a gas, partitioning to air is likely to occur with an environmental release. H(2)S inhalation PAL values for 24-hour exposure are PAL 1 = 1.2 ppm; PAL 2 = 7.0 ppm; and PAL 3 = 27 ppm; the 30-day and 90-day inhalation exposure values are PAL 1 = 0.85 ppm and PAL 2 = 3.0 ppm. PAL 3 values for 30-day and 90-day exposures are not recommended due to insufficient data. Long-term data were insufficient to estimate 2-year inhalation PALs.

Provisional Advisory Levels (PALs) for phosgene (CG).

The Provisional Advisory Level (PAL) protocol was applied to estimate inhalation exposure limits for phosgene (CG). Three levels (PAL 1, PAL 2, and PAL 3), distinguished by severity of toxic effects, are developed for 24-hour, 30-day, 90-day, and 2-year durations of potential drinking water and inhalation exposures for the general public. For background on the PAL program and a description of the methodology used in deriving PALs, the reader is referred to accompanying papers in this Supplement. Data on humans are limited to occupational exposures or accounts from the use of phosgene as a chemical warfare agent in World War I. Animal studies with phosgene show a steep dose-response curve for pulmonary edema and mortality, with little species variability in effects. Although immediately upon exposure lacrimation and upper respiratory irritation can occur, the main effect in the target organ, a progressive pulmonary edema, occurs after a latency period of 1-24 hours. PAL estimates were approved by the Expert Consultation Panel for Provisional Advisory Levels in May 2007. Exposure limits for oral exposure to CG are not developed due to insufficient data. PAL estimates for inhalation exposure to CG are presented: The 24-hour PAL values for severity levels 1, 2, and 3 are 0.0017, 0.0033 and 0.022 ppm, respectively. The 30- and 90-day PAL values are 0.0006 and 0.0012 ppm for the PAL 1 and 2 values, respectively. These inhalation values were also accepted as the 2-year PAL 1 and 2 values because severity of lesions in the key study did not increase when exposures were extended from 4 weeks to 12 weeks. Data were not available for deriving 30-day, 90-day, and 2-year PAL 3 values.

Health-based Provisional Advisory Levels (PALs) for homeland security.

The Homeland Security Presidential Directive #8 (HSPD-8) for National Emergency Preparedness was issued to " establish policies to strengthen the preparedness of the United States to prevent and respond to threatened or actual domestic terrorist attacks, major disasters, and other emergencies by requiring a national domestic all- hazards preparedness goal. "In response to HSPD-8 and HSPD-22 (classified) on Domestic Chemical Defense, the US Environmental Protection Agency (US EPA) National Homeland Security Research Center (NHSRC) is developing health-based Provisional Advisory Levels (PALs) for priority chemicals (including chemical warfare agents, pesticides, and toxic industrial chemicals) in air and drinking water. PALs are temporary values that will neither be promulgated, nor be formally issued as regulatory guidance. They are intended to be used at the discretion of risk managers in emergency situations. The PAL Program provides advisory exposure levels for chemical agents to assist in emergency planning and response decision-making, and to aid in making informed risk management decisions for evacuation, temporary re-entry into affected areas, and resumed-use of infrastructure, such as water resources. These risk management decisions may be made at the federal, state, and local levels. Three exposure levels (PAL 1, PAL 2, and PAL 3), distinguished by severity of toxic effects, are developed for 24-hour, 30-day, 90-day, and 2-year durations for potential exposure to drinking water and ambient air by the general public. Developed PALs are evaluated both by a US EPA working group, and an external multidisciplinary panel to ensure scientific credibility and wide acceptance. In this Special Issue publication, we present background information on the PAL program, the methodology used in deriving PALs, and the technical support documents for the derivation of PALs for acrylonitrile, hydrogen sulfide, and phosgene.

Pesticide mixtures potentiate the toxicity in murine thymocytes.

The immunotoxic risks of multiple pesticide exposure were evaluated. C57BL/6 mouse thymocytes were exposed to lindane, malathion, and permethrin, either separately or in mixtures of two pesticides, in vitro. These pesticide exposures caused both apoptotic and necrotic cell death in thymocytes as evaluated by flow cytometric analysis in combination with 7-aminoactinomycin-D (7-AAD), Annexin-V/propidium iodide (PI) staining assays and lactate dehydrogenase release assays. When cells exposed to mixtures of two pesticides, a significantly greater than additive interaction was observed in both apoptotic and necrotic populations of cells. The gel electrophoresis of DNA of cells showed DNA ladder formation with limited genomic DNA and increased laddering in mixture exposures. Based on these findings, it is suggested that these pesticides are potent immunotoxicants, in vitro, and that the mechanism of cytotoxicity observed upon exposure to these pesticides may, at least in part, be due to induction of apoptosis. We also provided evidence that induction of drug metabolizing mixed function oxidase system with lindane may, in part, be responsible for the potentiation of cytotoxicity in the combined exposures. As more information is obtained on the potential immunotoxic effects of pesticides, further insights will be gained for the risk assessment of these environmental pollutants.