Strategies to Protect the Health of Deployed U.S. Forces Assessing Health Risks to Deployed U.S. Forces: Workshop Proceedings (2000) / Chapter Skim
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6 Approaches for Using Toxicokinetic Information in Assessing Risk to Deployed U.S. Forces
6 Approaches for Using Toxicokinetic Information in Assessing Risk to Deployed U.S. Forces
Pages 113-149
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From page 113... ...
Continuous exposure forces the dynamic and kinetic time scales to become synchronized, thereby reducing complexity to three variables: dose, elect, and one time scale. Keeping one of those variables constant allows one to study the other two variables reproducibly under isoe~ective, isodosic, or isotemporal conditions.
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From page 114... ...
They do not realize that they are studying extreme parts of a spectrum under liminal conditions (e.g., a highly reversible elect on a short time scale) , and they use experimental models with insufficient time resolution.
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From page 115... ...
back to the ideal conditions, then any projection will also be possible in the opposite direction. Thus, it can be expected that the vast majority of experiments conducted under less-thanideal conditions will then become interpretable by using a related study, which has been conducted under ideal conditions.
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From page 116... ...
It is noteworthy that the various time-dependencies seldom run on the same time scale. Conceptually, K might also be viewed as a function of the dynamic change between absorption (Alec)
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From page 117... ...
Much more reasonable is Warren's (1900) analogy to P x V = k for ideal gases as a comparison to ideal conditions in toxicology.
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From page 118... ...
are highly irregular. Nevertheless, it is reasonable to expect that risk predictions will be possible for even the most irregular exposure scenarios once the reference points are established as dose- and time-responses under ideal conditions (toxicodynamic or toxicokinetic/toxicodynamic steady state)
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From page 119... ...
. Thus, in toxicology the dose is a pure variable, but there are many different processes occurring on different time scales yielding different ~cdt integrals leading to complex interactions, which can be described as c x to.
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One independent time scale is the half-life of the rate-determining step (toxicodynamic or toxicodynamic/ toxicokinetic) of the intoxication (intrinsic property of compound or organism)
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From page 121... ...
However, if there are three different rate-limiting processes occurring on different time scales in toxicokinetics and three different rate-limiting processes taking place on three different time scales in toxicodynamics, such a scenario would represent a formidable computational task for a theoretical treatise. Therefore, a practical approach would be to conduct experiments at toxicodynamic steady state (which of course would require a preexisting toxicokinetic steady state in many instances)
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From page 122... ...
(1977) have reported such data after continuous exposure of experimental animals to benzene and SO2 when the endpoint in question was measured immediately after termination of exposure (chronaxy, leukopenia)
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From page 123... ...
What is clear already at this junction is that the dimension of P x V is energy, whereas the dimension of c x t is energy x time, which is action and is called effect in toxicology (Figure 5~. DECISION TREE A recent series of articles explored how other disciplines deal with complex systems (Goldenfeld and Kandanoff 1999; Whitesides and Ismagilov 1999; Weng et al.
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From page 124... ...
FORCES: WORKSHOP PROCEEDINGS y = 1.09x - 191.97 rz = o.~O . /^ ~ _ 200 C: ~ t tm poke ~ d ay)
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From page 125... ...
The time course of oral absorption is limited by the dynamism of the gastrointestinal (GI) tract and the physicochemical properties of the chemicals being absorbed.
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From page 126... ...
x 5 d/wk x 52 wk x 45 yrs = 1.17 x 10~° fibers Amount that might be inhaled in 14 d: 1.17 x 10~° fibers In one day: 1.17 x 10~°/14 = 8.357 x 108 fibers/d Amount of air inhaled in 24 h: 20 m3 8.357 x 108/20 m3 = 4.178 x 107 fibers/m3, or 4.178 x 107/1 X 106 cm3 = 41.8 fibers/cm3 14-day deployment exposure limit (DEL) : 41.8 fibers/cm3 It is a risk-management decision how much reserve capacity needs to be retained for the remaining life expectancy.
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From page 127... ...
, on a log Cp versus time plot. For chemicals that are very rapidly cleared, excretion will not be rate-determining, because biotransformation is usually a slower process, and hence it will dominate the overall time course of elimination.
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From page 128... ...
According to these considerations, once a month exposure to very high concentrations of benzene would result in accumulation of residual damage (according to c x t after reaching steady state) , until the individuals aplastic anemia (or leukemia on still another time scale)
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From page 129... ...
Recovery is usually slower, making it most often the rate-determining step. The definition of toxicity as the accumulation of injury (occurring usually, but not always, according to the dynamic time scale of recovery)
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They do not bind to DNA, but due to their long half-life (dioxins) or continuous exposure (phorbol esters)
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From page 131... ...
However, binding of reactive organophosphates, such as soman to serine residues, occurs on a time scale of minutes as compared with normal degradation of enzymes, which proceed on a time scale of longer than a day. Thus, in such instances, synthesis of new enzymes, rather than their degradation, becomes rate-determining for recovery.
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From page 132... ...
This can occur simultaneously with the elimination of a compound or with a lag period (equal to the toxicodynamic half-life) , which is a measure of the reversibility or irreversibility of an effect.
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From page 133... ...
Continuous exposure forces the dynamic and kinetic time scales to become synchronized, thereby reducing complexity to three variables: dose, effect, and one time scale. Keeping one of those variables constant allows one to study the other variables reproducibly under isoeffective, isodosic, or isotemporal conditions.
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From page 134... ...
The three time scales are the toxicokinetic and toxicodynamic half lives and the frequency of exposure. Thus, there are three liminal conditions: 1.
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From page 135... ...
APPENDIX 1 Examples to Illustrate the Use of the Decision Tree Concept in Risk Analysis Dioxin (TCDD) Toxicodynamics half-life unknown, but unlikely to be rate-determining Injury Death: wasting, hemorrhage, anemia, cancer Incapacitation: little Residual damage: chloracne (human)
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at, ~ . 1~000 5,000 10,000 Days FIGURE 6 Schematic illustration of the effect of different halflives of TCDD on steady-state concentrations in humans and rats given the same daily dose rates.
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From page 137... ...
Assuming that risk is linearly decreasing, also below the threshold, this calculation would yield a risk of 0.4 x 10-6 for a daily exposure to 4.1 ng/kg of TCDD. According to the c x t concept, lung cancer could occur in a sensitive human being after 10,250,000 days, or 28,082 years, of exposure to TCDD at this daily dose rate.
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From page 138... ...
Adaptation: limited Pretreatment: Pretreatment with soman does not change its toxicity Pretreatment with agents, which bind to the same site reversibly provides possibility for therapeutic intervention Exercise: Increases rate of respiration and therefore will lead to higher systemic exposure Stress: Same as for exercise Temperature: Repair There is a temperature effect DNA repair: not critical Apoptosis: not critical Cell proliferation: coincidental impact Synthesis of new biological entity: slow (rate-determining) Cell Proliferation: This is not a critical step in the assessment of soman toxicity.
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From page 139... ...
As a first approximation, the daily reference dose needs to be divided further by the number of days exposure occurred. Oral 1-day deployment exposure limit (DEL)
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From page 140... ...
: 7 ,ug/m3 14-day DEL: 0.5 ,ug/m3 30-day DEL: 0.2 ,ug/m3 These values are DELs for continuous exposure. If exposure is intermittent, the following rule will provide protection: If exposure occurs outside of 6.62 recovery half-lives (3.3 days at a half-life of ~ 12 h)
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From page 141... ...
A single high dose exposure will not be much different from exposure to proportionally smaller daily dose rates. Thus, for these types of compounds, there is little difference between TWA and peak exposure.
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From page 142... ...
The half-life is probably very similar in humans because the mechanism of toxicity is the same and the rat's LD50 = 75 mg/kg is similar to the human's lethal dose _ 220 mg/kg. Inhalation TLV recommendation: 2 mg/m3,8-h TWA for 5 days/week for 45 years at 10 m3/8 h Total dose: 234,000 mg/70 kg person 3,343 mg/kg 1-day DEL by inhalation: 1 mg/m3 at 20 m3/24 h 14-day DEL by inhalation: 0.07 mg/m3 3-month DEL by inhalation: 0.03 mg/m3 This is the most conservative conversion, assuming continuous exposure.
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From page 143... ...
Therefore, in a deployment situation these values could be used as ceilings not to be exceeded. Because these values were derived with continuous exposure, the 1-hour DEL (continuous exposure)
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From page 144... ...
Unlike compounds with very long toxicokinetic half-lives (which amounts to continuous exposure) , both the frequency and duration and the kinetics of compounds are important when dynamics of the effects are rate-determining.
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From page 145... ...
. Different daily dose rates of diethylnitros amine yielded a c x t = k equal to 73,248 + 5,234 (SE)
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From page 146... ...
If needed, the oral data apply. Very short toxicodynamic half-lives The distinction between toxicokinetic and toxicodynamic half lives becomes fuzzy for compounds of very short recovery half-lives (<3.6 hi, because for both of them another time scale (frequency of exposure)
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From page 147... ...
Part 1: Effects of continuous exposure.
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From page 148... ...
1998. Derivation of an occupational exposure limit (OEL)
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From page 149... ...
APPROACHES FOR USING TOXICOKINETIC INFORMATION IN ASSESSING RISK 149 Weber, L.W., S.W. Ernst, B.U.
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