Cheryl B Bast

Establishing a Point of Departure for Risk Assessment Using Acute Inhalation Toxicology Data

A simple method is presented for estimating a non-lethal level for inhalation toxicity studies. By reviewing 209 LC(50) studies representing 96 chemicals that also reported a non-lethal level, it has been shown that taking 1/3 of the LC(50) is a conservative estimate for a non-lethal exposure level. This approach was also compared to studies with LC(01) and BMCL(05) calculations. In the 38 studies that reported either of these values, again taking 1/3 of the LC(50) provided a more conservation estimate for the non-lethal threshold. The studies included time intervals from 5min out to 8h and utilized multiple species such as the rat, mouse, hamster, guinea pig and dog. In all but 13 cases, taking 1/3 of the LC(50) provided a more conservative estimate for a non-lethal exposure level compared to the experimentally observed value. In all but one of the 13 cases, the higher values were consequences of the selection of the exposure levels.

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.

Mustards and Vesicants

Vesicants (sulfur mustards, lewisite, and nitrogen mustards) are chemicals that cause blistering of the skin. Developed as chemical warfare agents, their biological activity is complex and not fully understood. These vesicants, whether in liquid or vapor form, are capable of causing injury to most tissue. Contact with the skin results in erythema and blistering. Exposure to vapors produces ocular and respiratory effects that occur at exposures below those causing dermal effects. Systemic and long-lasting effects may occur, especially following acute exposures that result in severe injury. Multiorgan involvement and fluid loss shock resulting in death may follow severe exposures. As alkylating agents, all of the mustards are known to be potential carcinogens. The carcinogenic potential of lewisite in humans is equivocal. Animal toxicity data are available for vesicants. Data for sulfur mustard and lewisite are more extensive than for nitrogen mustards. Results of tests with human volunteers and occupational exposure information are also available. These data collectively have provided a basis for the development of exposure standards, guidelines, and criteria for use in emergency planning and emergency response, as well as remediation efforts. The mode of action of the vesicants is complex, not fully understood, and represents an ongoing area of investigation especially with respect to treatment of vesicant-induced injury. In fact, most currently conducted research focuses on these areas. Prevention of exposure and decontamination are critical initial steps in eliminating or minimizing injury. With the exception of arsenic chelating antidotes (e.g., British anti-lewisite, or BAL) for lewisite, no antidotes exist for vesicant agents. Medical management currently focuses on palliative treatment of signs and symptoms.

Chapter 8 – Mustards and Vesicants

Vesicants (sulfur mustards, lewisite, and nitrogen mustards) are chemicals that cause blistering of the skin. Developed as chemical warfare agents, their biological activity is complex and not fully understood. These vesicants, whether in liquid or vapor form, are capable of causing injury to most tissue. Contact with the skin results in erythema and blistering. Exposure to vapors produces ocular and respiratory effects that occur at exposures below those causing dermal effects. Systemic and long-lasting effects may occur, especially following acute exposures that result in severe injury. Multiorgan involvement and fluid loss shock resulting in death may follow severe exposures. As alkylating agents, all of the mustards are known to be potential carcinogens. The carcinogenic potential of lewisite in humans is equivocal. Animal toxicity data are available for vesicants. Data for sulfur mustard and lewisite are more extensive than for nitrogen mustards. Results of tests with human volunteers and occupational exposure information are also available. These data collectively have provided a basis for the development of exposure standards, guidelines, and criteria for use in emergency planning and emergency response, as well as remediation efforts. The mode of action of the vesicants is complex, not fully understood, and represents an ongoing area of investigation especially with respect to treatment of vesicant-induced injury. In fact, most currently conducted research focuses on these areas. Prevention of exposure and decontamination are critical initial steps in eliminating or minimizing injury. With the exception of arsenic chelating antidotes (e.g., British anti-lewisite, or BAL) for lewisite, no antidotes exist for vesicant agents. Medical management currently focuses on palliative treatment of signs and symptoms.