Review of Acute Human-Toxicity Estimates for Selected Chemical-Warfare Agents (1997)
Chapter: Summary
Summary
No reliable acute-exposure1 standards have been established for the particular purpose of protecting soldiers from toxic exposures to chemical-warfare (CW) agents. Some human-toxicity estimates are available for the most common CW agents—organophosphorus nerve agents and vesicants; however, most of those estimates were developed for offensive purposes (that is, to kill or incapacitate the enemy) and were intended to be interim values only.
The U.S. Army's original purpose for developing human-toxicity estimates for CW agents was to enable it to predict the number of casualties that would occur during an offensive action in which the goal was to kill or incapacitate a certain fraction of the enemy forces (for example, killing or incapacitating a minimum of 50% of the least-sensitive (most-resistant) individuals). Such an approach would actually result in more than half of the exposed individuals dying (the "bonus effect"), because a certain percentage of those exposed would be expected to be more susceptible than the least-sensitive individual. Thus, exposure under the Army's original estimates would result in substantial "over-kill." These estimates understate the toxicity of the agents and therefore are inappropriate for protecting soldiers.
Because of the possibility of a chemical attack by a foreign power, the Army's Office of the Surgeon General asked the Army's Chemical Defense Equipment Process Action Team (CDEPAT) to review the toxicity data for the nerve agents GA (tabun), GB (sarin), GD (soman), GF, and VX, and the vesicant agent sulfur mustard (HD) and to establish a set of exposure limits that would be useful in protecting soldiers from toxic exposures to those agents. In the 1994 report entitled Review of Existing Toxicity Data and Human Estimates for Selected Chemical Agents and Recommended Human Toxicity Estimates Appropriate for Defending the Soldier, the team concluded that some of the existing human-toxicity estimates are too high and are inappropriate for use in protecting soldiers. In those cases, CDEPAT proposed new estimates for various routes of exposure—percutaneous vapor, vapor inhalation, and percutaneous liquid exposures. The proposed human-toxicity estimates are only for healthy male military personnel. They must not be used for civilians.
Before making a decision on acceptance of the human-toxicity estimates proposed by CDEPAT, the Department of the Army requested that the National Research Council (NRC) independently review the CDEPAT report to determine the scientific validity of the proposed estimates. The NRC assigned this project to the Committee on Toxicology (COT) of the Board on Environmental Studies and Toxicology. The COT convened the Subcommittee on Toxicity Values for Selected Nerve and Vesicant Agents, which prepared this report. Members of the subcommittee were selected for their recognized expertise in the fields of toxicology, medicine, pathology, biostatistics, and risk assessment. The subcommittee was charged to review the Army's proposed human-toxicity estimates for GA, GB, GD, GF, VX, and HD. Specifically, the subcommittee was charged with the following tasks:
- Review the scientific protocols and quality of the toxicity data used in revising the human-toxicity estimates for acute exposures.
- Review the toxicity estimates for mild and nonsevere effects and for severe and lethal effects.
- Review the methods used in deriving the human-toxicity estimates for acute exposures.
- Determine the appropriateness of the assumptions made in deriving the human-toxicity estimates for acute exposures.
The subcommittee was not asked to recommend new toxicity estimates
or to address the policy or operational consequences of lowering the proposed human-toxicity estimates. The subcommittee's evaluations of CDEPAT's proposed estimates for GA, GB, GD, GF, VX, and HD are summarized in Tables 1 through 6.
The subcommittee's conclusions concerning the scientific validity of the proposed CDEPAT estimates are grouped in four categories: (1) some estimates were judged to be scientifically valid; (2) other estimates were judged adequate to serve as interim estimates until further research is conducted; (3) some estimates need to be lowered; and (4) a few estimates need to be raised.
The toxicity data that CDEPAT used to derive its proposed estimates were generated primarily from a data base developed from the 1930s to the 1960s. The existing human-toxicity estimates were based on experiments performed 30–40 years ago using various animal species in often poorly controlled studies with vastly different protocols. In reviewing the available toxicity data for the six CW agents, the subcommittee recognized that the quality of the relevant toxicity data is marginal, but it also recognized that the Army needs "best estimates" to protect its troops from exposure. For each chemical agent, data were available for only a few adverse health effects, such as death, incapacitation, cholinesterase (ChE) inhibition, miosis (a decrease in pupil size), and rhinorrhea (running nose), vesication, and erythema. Thus, even though the subcommittee concluded that some of CDEPAT's proposed estimates are scientifically valid, those conclusions are based on a limited toxicity data base. By current standards of toxicology, the toxicity data base for the agents is inadequate, and such inadequacy is a major obstacle to the Army in developing human-toxicity estimates with statistical confidence and in developing risk-management strategies.
The subcommittee recommends that the Army convene an expert panel to develop a research strategy for deriving more scientifically sound toxicity values for the agents of concern. The panel should first consider the use of such techniques as structure-activity relationships, the uncertainty factors, and in vitro systems for estimating human-toxicity values for CW agents.
If these approaches do not appear to be useful, animal and human experimentation may be recommended. Although additional research is clearly desirable to provide improved confidence in existing data, such research should not be performed on laboratory animals until expert judgment documents the need on a case-by-case basis. It must be documented that the data to be obtained from laboratory animals is needed to make a significant improvement in the protection of human health.
TABLE 1 Evaluation of Human-Toxicity for GA
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Human-Toxicity Estimates for GA |
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Toxicity Type |
Route and Form of Exposure |
Existing Estimates |
CDEPAT's Proposed Estimates |
Subcommittee's Evaluation of Proposed Estimates for GA |
Rationale for Subcommittee's Evaluation |
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LCt50a |
Percutaneous, vapor |
20,000 mg-min/m3 |
15,000 mg-min/m3 |
Proposed estimate is scientifically valid |
Proposed estimate supported by human data |
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Inhalation, vapor |
135 mg-min/m3 |
70 mg-min/m3 |
Proposed estimate should be lowered |
Because of inadequate data on GA for this route, CDEPAT derived the estimate by assuming that GA is 0.5 times as toxic as GB; approach reasonable but estimate should be lowered because of recommended lowering of LCt50 for GB for this route; further research recommended |
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ECt50b |
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Threshold effects |
Percutaneous, vapor |
None |
2,000 mg-min/m3 |
Proposed estimate is scientifically valid |
ChE inhibition data used for proposing new recommendation |
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Severe effects |
Inhalation, vapor |
None |
50 mg-min/m3 |
Proposed estimate should be lowered |
CDEPAT's proposed estimate based on a study that indicated the ratio of ICt50e/LC50 is 0.75; that assumption used to establish ECt50. for severe effects; the subcommittee recommends that the ECt50 estimate be lowered to correspond to the lowered estimate for LCt50; further research recommended |
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Mild effects |
Inhalation, vapor |
0.9 mg-min/m3 |
0.5 mg-min/m3 |
Proposed estimate should be raised |
Human data show that humans can tolerate higher exposures; further research recommended |
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Human-Toxicity Estimates for GA |
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Toxicity Type |
Route and Form of Exposure |
Existing Estimates |
CDEPAT's Proposed Estimates |
Subcommittee's Evaluation of Proposed Estimates for GA |
Rationale for Subcommittee's Evaluation |
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LD50c |
Percutaneous, liquid |
1,500 mg for 70-kg man |
1,500 mg for 70-kg man |
Proposed estimate should be lowered |
No uncertainty factors used in lieu of limited animal data for proposed estimate; further research recommended |
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ED50d |
Percutaneous, liquid |
None |
880 mg for 70-kg man |
Proposed estimate should be lowered |
In the absence of adequate human or animal data for this effect, CDEPAT established the estimate by assuming ID50f/LD50 ratio of 0.6 to estimate ED50; the subcommittee recommends that the ED50 estimate be lowered to correspond to the lowered estimate for LD50; further research recommended |
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a LCt50: Vapor exposure that produces lethality in 50% of the exposed animals. Ct refers to the product of concentration (c) and exposure time (t). Note that Ct is not necessarily a constant. b ECt50: Percutaneous vapor exposure or inhalation vapor exposure causing a defined effect (e.g., incapacitation, severe effects, mild effects, threshold effects). c LD50: Liquid dose causing lethality in 50% of the exposed animals. d ED50: Liquid dose causing a defined effect in 50% of the exposed animals. e ICt50: Vapor exposure that produces incapacitation in 50% of the exposed population. f ID50: Liquid dose causing incapacitation in 50% of the exposed population. |
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TABLE 2 Evaluation of Human-Toxicity Estimates for GB
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Human-Toxicity Estimates for GB |
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Toxicity Type |
Route and Form of Exposure |
Existing Estimates |
CDEPAT's Proposed Estimates |
Subcommittee's Evaluation of Proposed Estimates for GA |
Rationale for Subcommittee's Evaluation |
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LCt50a |
Percutaneous, vapor |
15,000 mg-min/m3 |
10,000 mg-min/m3 |
Proposed estimate is scientifically valid |
Proposed estimate supported by studies in monkeys and humans |
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Inhalation, vapor |
70 mg-min/m3 |
35 mg-min/m3 |
Proposed estimate should be lowered |
Estimate too high because human studies show 100% lethality at 40 mg-min/m3 |
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ECt50b |
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Threshold effects |
Percutaneous, vapor |
None |
1,200 mg-min/m3 |
Proposed estimate is scientifically valid |
Estimate supported by studies of ChE inhibition in humans; further research recommended |
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Severe effects |
Inhaiation, vapor |
35 mg-min/m3 |
25 mg-min/m3 |
Proposed estimate should be lowered |
ECt50/LCt50 ratio of 0.7 used to develop estimate; LCt50 for this route of exposure was lowered; therefore, ECt50 should be lowered correspondingly; further research recommended |
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Mild effects |
Inhalation, vapor |
2 mg-min/m3 |
0.5 mg-min/m3 |
Proposed estimate should be raised |
No effects in humans at 0.5 mg-min/m3; effects begin to appear at |
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LD50c |
Percutaneous, liquid |
1,700 mg for 70-kg man |
1,700 mg for 70-kg man |
Low confidence in proposed estimate; proposed estimate should serve as interim value |
Estimate based on a ratio of ChE inhibition in rabbits and humans; however, human data concerning the relation between ChE inhibition and adverse effects are inconsistent; further research recommended |
2 mg-min/m3; further research recommended|
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Human-Toxicity Estimates for GB |
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Toxicity Type |
Route and Form of Exposure |
Existing Estimates |
CDEPAT's Proposed Estimates |
Subcommittee's Evaluation of Proposed Estimates for GA |
Rationale for Subcommittee's Evaluation |
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ED50d |
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Severe effects |
Percutaneous, liquid |
None |
1,000 mg for 70-kg man |
Proposed estimate should serve as interim value |
In the absence of adequate data on GB for this effect, CDEPAT assumed that the ratio of lD50c/LD50 is 0.6 and used that to estimate the ED50 values; further research recommended |
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a LCt50: Vapor exposure that produces lethality in 50% of the exposed animals. Ct refers to the product of concentration (c) and exposure time (t). Note that Ct is not necessarily a constant. b ECt50: Percutaneous vapor exposure or inhalation vapor exposure causing a defined effect (e.g., incapacitation, severe effects, mild effects, threshold effects). c LD50: Liquid dose causing lethality in 50% of the exposed animals. d ED50: Liquid dose causing a defined effect in 50% of the exposed animals. c ID50: Liquid dose causing incapacitation in 50% of the exposed population. |
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TABLE 3 Evaluation of Human-Toxicity Estimates for GD
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Human-Toxicity Estimates for GD |
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Toxicity Type |
Route and Form of Exposure |
Existing Estimates |
CDEPAT's Proposed Estimates |
Subcommittee's Evaluation of Proposed Estimates for GA |
Rationale for Subcommittee's Evaluation |
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LCt50a |
Percutaneous, vapor |
None |
2,500 mg-min/m3 |
Proposed estimate is scientifically valid |
Proposed estimate based on assumption that GD is 4 times more toxic than GB for percutaneous exposure |
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Inhalation, vapor |
70 mg-min/m3 |
35 mg-min/m3 |
Proposed estimate should be lowered |
Proposed estimate based on the assumption that GD and GB are equipotent via this route; subcommittee recommends that LCt50 estimate for GD be lowered to correspond to lowered estimate for GB; further research recommended |
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ECt50b |
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Threshold effects |
Percutaneous, vapor |
None |
300 mg-min/m3 |
Proposed estimate should serve as an interim value |
In the absence of adequate human or animal data, proposed estimate based on assumption that GD is 4 times more toxic than GB for percutaneous exposure; further research recommended |
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Severe effects |
Inhalation, vapor |
35 mg-min/m3 |
25 mg-min/m3 |
Proposed estimate should be lowered |
In the absence of adequate human or animal data, proposed estimate based on assumption that potencies of GD and GB are comparable; ECt 50 estimate for GD should be lowered to correspond to the lowered estimate for GB; further research recommended |
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Human-Toxicity Estimates for GD |
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Toxicity Type |
Route and Form of Exposure |
Existing Estimates |
CDEPAT's Proposed Estimates |
Subcommittee's Evaluation of Proposed Estimates for GA |
Rationale for Subcommittee's Evaluation |
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Mild effects |
Inhalation, vapor |
None |
0.2 mg-min/m3 |
Proposed estimate should be raised |
In the absence of adequate human or animal data, proposed estimate based on assumption that GD is 2.5 times more potent than GB for miotic effects; subcommittee recommends that the LCt50 estimate for GD be raised to correspond to the recommended raised estimate for GB; further research recommended |
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LD50c |
Percutaneous, liquid |
350 mg for 70-kg man |
350 mg for 70-kg man |
Proposed estimate should serve as an interim value |
Because of wide range of LD50 values in animals, subcommittee's confidence in the proposed estimate is low; CDEPAT's proposed estimate of 350 mg for 70-kg man should serve as an interim value; further research recommended |
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ED50d |
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Severe effects |
Percutaneous, liquid |
None |
200 mg for 70-kg man |
Proposed estimate should serve as an interim value |
In the absence of adequate human or animal data, proposed estimate was derived using the ID50e/LD50 ratio of 0.6; the subcommittee recommends that CDEPAT's proposed estimate serve as an interim value; further research recommended |
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a LCt50: Vapor exposure that produces lethality in 50% of the exposed animals. Ct refers to the product of concentration (c) and exposure time (t). Note that Ct is not necessarily a constant. b ECt50: Percutaneous vapor exposure or inhalation vapor exposure causing a defined effect (e.g., incapacitation, severe effects, mild effects, threshold effects). c LD50: Liquid dose causing lethality in 50% of the exposed animals. d ED50: Liquid dose causing a defined effect in 50% of the exposed animals. c ID50: Liquid dose causing incapacitation in 50% of the exposed population. |
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TABLE 4 Evaluation of Human-Toxicity Estimates for GF
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Human-Toxicity Estimates for GF |
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Toxicity Type |
Route and Form of Exposure |
Existing Estimates |
CDEPAT's Proposed Estimates |
Subcommittee's Evaluation of Proposed Estimates for GA |
Rationale for Subcommittee's Evaluation |
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LCt50a |
Percutaneous, vapor |
15,000 mg-min/m3 |
2,500 mg-min/m3 |
Proposed estimate should serve as an interim value |
Rationale for the CDEPAT estimate not supported by data; further research recommended |
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Inhalation, vapor |
None |
35 mg-min/m3 |
Proposed estimate should be lowered |
In the absence of adequate data, proposed estimate based on assumption that GF, GD, and GB are equipotent; approach is reasonable; because LCt50 for GB was recommended to be lowered, proposed value for GF should be lowered correspondingly; further research recommended |
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ECt50b |
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Threshold effects |
Percutaneous, vapor |
None |
300 mg-min/m3 |
Proposed estimate should serve as an interim value |
Proposed estimate based on assumption that GF and GD are equipotent; approach is reasonable; further research recommended |
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Severe effects |
Inhalation, vapor |
None |
25 mg-min/m3 |
Proposed estimate should be lowered |
In the absence of adequate data, proposed estimate based on assumption that GF, GD, and GB are equipotent; approach is reasonable; because ECt50s for severe effects for GB and GD were recommended to be lowered, proposed value for GF should be lowered correspondingly; further research recommended |
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Human-Toxicity Estimates for GF |
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Toxicity Type |
Route and Form of Exposure |
Existing Estimates |
CDEPAT's Proposed Estimates |
Subcommittee's Evaluation of Proposed Estimates for GA |
Rationale for Subcommittee's Evaluation |
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Mild effects |
Inhalation, vapor |
None |
0.2 mg-min/m3 |
Proposed estimate should be raised |
In the absence of adequate human or animal data, the proposed estimate based on assumption that GF and GD are equipotent; approach is reasonable; because ECt50 for mild effects for GD was recommended to be raised, proposed value for GF should be raised correspondingly; further research recommended |
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LD50c |
Percutaneous, liquid |
None |
350 mg for 70-kg man |
Proposed estimate should serve as an interim value |
In the absence of adequate human or animal data, proposed estimate based on assumption that GF and GD are equipotent; approach is reasonable; further research recommended |
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ED50d |
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Severe effects |
Percutaneous, liquid |
None |
200 mg for 70-kg man |
Proposed value should serve as an interim value |
In the absence of adequate human or animal data, the proposed estimate based on assumption that GF and GD are equipotent; approach is reasonable; further research recommended |
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a LCt50: Vapor exposure that produces lethality in 50% of the exposed animals. Ct refers to the product of concentration (c) and exposure time (t). Note that Ct is not necessarily a constant. b ECt50: Percutaneous vapor exposure or inhalation vapor exposure causing a defined effect (e.g., incapacitation, severe effects, mild effects, threshold effects). c LD50: Liquid dose causing lethality in 50% of the exposed animals. d ED50: Liquid dose causing a defined effect in 50% of the exposed animals. |
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TABLE 5 Evaluation of Human-Toxicity Estimates for VX
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Human-Toxicity Estimates for VX |
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Toxicity Type |
Route and Form of Exposure |
Existing Estimates |
CDEPAT's Proposed Estimates |
Subcommittee's Evaluation of Proposed Estimates for GA |
Rationale for Subcommittee's Evaluation |
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LCt50a |
Percutaneous, vapor |
None |
150 mg-min/m3 |
Proposed estimate should be considered an interim value |
Degree of confidence in data is low to moderate; further research recommended |
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Inhalation, vapor |
30 mg-min/m3 |
15 mg-min/m3 |
Proposed estimate should be lowered |
Degree of confidence in data is low to moderate; further research recommended |
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ECt50b |
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Threshold effects |
Percutaneous, vapor |
None |
10 mg-min/m3 |
Proposed estimate should be considered an interim value |
Degree of confidence in data is low; a no-observed-adverse-effect level (NOAEL) was not defined; further research recommended |
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Severe effects |
Percutaneous, vapor |
None |
25 mg-mill/m3 |
Proposed estimate should be considered an interim value |
Degree of confidence low to moderate; further research recommended |
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Inhalation, vapor |
25 mg-min/m3 |
10 mg-min/m3 |
Proposed estimate should be considered an interim value |
Insufficient data; further research recommended |
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Mild effects |
Inhalation, vapor |
0.09 mg-min/m3 |
0.09 mg-min/m3 |
Proposed estimate is scientifically valid |
Available human data support the proposed estimate |
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LD50c |
Percutaneous, liquid |
10 mg/70-kg man |
5 mg/70-kg man |
Proposed estimate should be lowered |
Animal data indicate that the proposed estimate is too high; furthermore, no uncertainty factor used in lieu of variability associated with dermal penetration of various regions of body; further research recommended |
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Human-Toxicity Estimates for VX |
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Toxicity Type |
Route and Form of Exposure |
Existing Estimates |
CDEPAT's Proposed Estimates |
Subcommittee's Evaluation of Proposed Estimates for GA |
Rationale for Subcommittee's Evaluation |
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ED50d |
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Severe effects |
Percutaneous, liquid |
5 mg/70-kg man |
2.5 mg/70kg man |
Proposed estimate should be lowered |
The ED50 is based on the ID50e/LD50 ratio; the subcommittee recommends that the LD50 be lowered, therefore, the ED50 should be lowered correspondingly; further research recommended |
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a LCt50: Vapor exposure that produces lethality in 50% of the exposed animals. Ct refers to the product of concentration (c) and exposure time (t). Note that Ct is not necessarily a constant. b ECt50: Percutaneous vapor exposure or inhalation vapor exposure causing a defined effect (e.g., incapacitation, severe effects, mild effects, threshold effects). c LD50: Liquid dose causing lethality in 50% of the exposed animals. d ED50: Liquid dose causing a defined effect in 50% of the exposed animals. e ID50: Liquid dose causing incapacitation in 50% of the exposed population. |
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TABLE 6 Evaluation of Human-Toxicity Estimates for HD
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Human-Toxicity Estimates for HD |
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Toxicity Type |
Route and Form of Exposure |
Existing Estimates |
CDEPAT's Proposed Estimates |
Subcommittee's Evaluation of Proposed Estimates for GA |
Rationale for Subcommittee's Evaluation |
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LCt50a |
Percutaneous, vapor |
10,000 mg min/m3 |
5,000 mg-min/m3 |
Proposed estimate should be lowered |
Estimate might be too high because data from the most-sensitive species (rats and mice) not used; further research recommended |
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Inhalation, vapor |
1,500 mg min/m3 |
900 mg-min/m3 |
Proposed estimate is scientifically valid |
CDEPAT averaged LCt50 data in several animal species; in the absence of data on humans, that approach is reasonable |
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ECt50b |
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Threshold effects |
Percutaneous, vapor |
None |
50 mg-min/m3 (moderate temperature); 25 mg-min/m3 (hot temperature) |
Proposed estimates should serve as interim values |
In the absence of details on studies on which estimates were based, proposed estimate should be considered interim value; further research recommended |
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Severe effects |
Percutaneous, vapor |
2,000 mg-min/ m3 (moderate temperature) 1,000 mg min/ m3 (hot temperature) |
500 mg-min/m3 (moderate temperature); <200 mg-min/m3 (hot temperature) |
Proposed estimates are scientifically valid |
Estimates based on human studies |
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Human-Toxicity Estimates for HD |
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Toxicity Type |
Route and Form of Exposure |
Existing Estimates |
CDEPAT's Proposed Estimates |
Subcommittee's Evaluation of Proposed Estimates for GA |
Rationale for Subcommittee's Evaluation |
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Inhalation, vapor |
200 mg-min/ m3 (moderate temperature) |
100 Mg-Min/m3 moderate temperature) |
Proposed estimate is scientifically valid |
Proposed estimate supported by human data |
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Mild effects |
Inhalation, vapor |
>50 mg min/m3 |
25 mg-min/m3 |
Proposed estimate is scientifically valid |
Proposed estimate supported by human data |
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LD50c |
Percutaneous, liquid |
7,000 mg for 70-kg man |
1,400 mg for 70kg man |
Proposed estimate is scientifically valid |
Proposed estimate supported by a study in dogs |
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ED50d |
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Severe effects |
Percutaneous, liquid |
None |
610 mg for 70-kg man |
Proposed estimate is scientifically valid; however, it should be rounded to 600 mg for a 70-kg man to avoid appearance of precision that is not there |
Proposed estimate supported by human data |
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a LCt50: Vapor exposure that produces lethality in 50% of the exposed animals. Ct refers to the product of concentration (c) and exposure time (t). Note that Ct is not necessarily a constant. b ECt50 Percutaneous vapor exposure or inhalation vapor exposure causing a defined effect (e.g., incapacitation, severe effects, mild effects, threshold effects). c LD50: Liquid dose causing lethality in 50% of the exposed animals. d ED50: Liquid dose causing a defined effect in 50% of the exposed animals. |
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The experimental designs should include the following:
- Define if and when experiments with humans are appropriate.
- In the absence of human experimentation, define the most appropriate animal model for each specific toxicity value and agent, including the end points to be observed.
- Define the adequacy of the design in determining the toxicity values for healthy female as well as healthy male military personnel.
- Define the requirements for observation of reversibility of adverse health effects.
- Identify adverse health effects at the low end of the dose-response curve to determine threshold exposure levels.
- Identify confidence limits for the proposed estimates as a measure of the uncertainty of the estimated incidence of toxic effects.
- Identify potentiation or antagonistic effects from exposures to mixtures of chemical agents.
- Identify more-sensitive biological markers of exposure and effects for CW agents.
