Methods for Developing Spacecraft Water Exposure Guidelines (2000) / Chapter Skim
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4 Risk Assessment Methods for Determining Spacecraft Water Exposure Guidelines
4 Risk Assessment Methods for Determining Spacecraft Water Exposure Guidelines
Pages 75-107
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From page 75... ...
For space travel, the anticipated durations are substantially less than a lifetime, but the absolute lifetime risk of adverse health effects is still the focus of the risk assessment. For adverse effects that are transitory and only mildly debilitating, the intent is to ensure that exposure to substances that cause such effects is restricted to amounts that wiD not impede the normal performance of duties aboard spacecraft.
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From page 76... ...
HISTORICAL PERSPECTIVE Risk Assessment for Noncarcinogenic Effects For toxic effects other than cancer, the practice of risk assessment has been to set acceptable exposure by dividing no-observed-adverse-effect levels (NOAELs) obtained from human studies or animal experiments by a set of uncertainty factors (sometimes caned "safety" factors)
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From page 77... ...
Risk Assessment for Carcinogenic Effects It has been assumed traditionally that threshold doses do not exist for carcinogenic effects, particularly those considered to result from genotoxicity. For this reason, it has been considered infeasible to establish low exposure limits that correspond to zero risk.
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From page 78... ...
Also, in general, no uncertainty factor is used for human variation in sensitivity to a substance's carcinogenic effects. However, variation in the experimental data is a source of uncertainty that is recognized for carcinogenic effects through the use of statistical confidence limits instead of central estimates.
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From page 79... ...
Proponents of low-dose linear extrapolation have questioned the presumption by NOAEL proponents that zero-risk limits (thresholds) can be established based on experimental observations; proponents of the NOAEL-uncertainty factor approach have questioned the presumption by modeling proponents that precise risks can be attached to doses below the observed experimental range.
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From page 80... ...
Experimental variation, however, is an important source of uncertainty that has been neglected heretofore in risk assessment for noncarcinogenic effects. The BMD originally was defined as a statistical lower confidence limit on the EDp, for 0.01 < p < 0.10.
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From page 81... ...
The resulting exposure guidance levels do not have specific risk connotations attached to them, but they are simply expected to reflect adequate safety. When sufficient data are available, the unified BMD-based method for calculating acceptable human exposures is recommended for determining maximum contamination in water aboard spacecraft—spacecraft water exposure guidelines (SWEGs)
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From page 82... ...
It is desirable that methods used to fit dose-response models to observed data include provisions for calculating statistical confidence limits, because experimental variation is a source of uncertainty that must be considered. Instead of using a formal statistical lower confidence limit on a BMDp as a starting point, one could calculate a central estimate of the BMDp, and reduce it by an uncertainty factor to account for experimental variation.
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From page 83... ...
Estimating BMD~ for Various Toxic Effects Traditional methods of dose-response modeling for binom~aDy distributed random variables can be used to estimate carcinogenic effects and other quantal toxic responses (lethality, some mutagenic responses) for which subjects are assumed to respond independently from one another.
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From page 84... ...
Hence, the question of whether to use target tissue dose or administered dose for dose-response modeling depends on the degree of confidence that can be placed in the pharmacokinetic model. Differences in Duration For toxic effects that are believed neither to accumulate nor to increase in adversity over time, a single exposure level for a toxicant can be used for SWEGs of different durations.
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From page 85... ...
However, like the NRC Subcommittee on Emergency Exposure Guidance Levels (NRC 1986) , the subcommittee on SMACs does consider the use of C x T = K appropriate for extrapolating between two exposures that are relatively short term with respect to clearance or repair rate.
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From page 86... ...
for converting lifetime daily exposure to carcinogens to exposures applicable to the shorter durations associated with spaceflight is based on a multistage model (KodeD et al.
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From page 87... ...
Hence, quite often, in the absence of adequate pharmacokinetic or pharmacodynam~c information to enable determination of an appropriate conversion factor, an assumption of concentration equivalence between species is made, and extrapolation is done on a straight concentration basis (e.g., parts per minion in food, air, or water)
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From page 88... ...
A primary concern is the effectiveness of systems in producing or limiting exposure in the spacecraft to specified levels. Clearly, a decision of what constitutes acceptable exposure must be considered in the design phase of mechanical and other systems.
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From page 89... ...
, a formal statistical lower confidence limit on the BMDp—say the LBMDp could be calculated and then used to back-calculate the appropriate factory = CBMDp/LBMDp, by which to reduce the central estimate of the BMDp to account for experimental variation. Although that approach is exactly the same as calculating a formal statistical lower limit in the first place, it does have the advantage of conveying the size of the uncertainty factor, A, that is used to control for experimental variation.
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From page 90... ...
in the derivation of SMACs to reflect the uncertainty in NOAELs based on a limited number of human subjects. The smaH-n factor also could be used in the derivation of SWEGs if insufficient data are available to calculate a specific BMDp.
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From page 91... ...
Hence, astronauts in space win be in an altered homeostatic state and might experience increased sensitivity to the toxic effects of contam~nated water. It is important to reduce chemical exposure relative to what would be acceptable on Earth for toxic effects that are influenced by the physiologic changes induced by spaceflight.
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From page 92... ...
Although the intent of the procedure recommended for setting SWEGs is to provide a unified approach that applies to all types of toxic effects, there is one possible point of departure between carcinogenic and noncarcinogenic effects. That is, because of the severity and irreversibility of cancer, some risk assessors recommend that exposure limits based on carcinogenic effects be reduced by an additional factor to take this into account (Renwick 1995; Gaylor et al.
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From page 93... ...
suggest using a reduced, combined uncertainty factor to set acceptable limits. Assum~ng that individual uncertainty factors are lognormally distributed (Dourson et al.
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From page 94... ...
. The rationale for the combined uncertainty factor F is that, if estimates of the mean and standard deviation of the individual distributions of uncertainty are available, then statistical techniques for estimating upper tolerance limits of distributions of sums of independent random variables can be used to calculate a reduced overall uncertainty factor (that is less than the product of individual factors)
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From page 95... ...
. However, an exposure duration uncertainty factor, such as the subchronic-to-chronic factor, might be needed for spaceflights of 1000 d.
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From page 96... ...
and by EPA for chemical mixtures that occur in any exposure medium (EPA 1986~. For each group with a particular mode of action, a separate group limit calculation should be made for restricting the concentrations of these species in spacecraft water.
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From page 97... ...
However, any potential SWEG that is within a factor of 3 of the lowest potential SWEG is also considered a determining factor of that SWEG. Comparisons with Established Values AD documents used to establish previous industrial or public-health exposure guidance levels for water contaminants should be reviewed before SWEG values are set for NASA.
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From page 98... ...
Concomitant with the refinement of BBDR models has been the development of ever more sophisticated physiologically based pharmacokinetic (PBPK) models, which have been used to obtain better estimates of target tissue doses for risk assessment (Andersen et al.
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From page 99... ...
Most if not all applications of ordinal regression have been restricted to acute toxic effects, specifically excluding carcinogenic effects. Whether ah types of toxic effects, including cancer, can be modeled simultaneously using ordinal regression is still undetermined.
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From page 100... ...
However, the use of estimated change-points for threshold effects and BMDps for nonthreshold effects would destroy the unity of the proposed approach for ah types of toxic effects, including threshold and nonthreshold effects. SUMMARY Using the process of risk assessment to establish SWEGs involves several important steps.
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From page 101... ...
1996. Noncancer risk assessment: A probabilistic alternative to current practice.
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From page 102... ...
1997. National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances.
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From page 103... ...
1999. A unified approach to risk assessment for cancer and noncancer endpoints based on benchmark doses and uncertainty/safety factors.
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From page 104... ...
1993. Upper confidence limits on excess risk for quantitative responses.
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From page 105... ...
.1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants.
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From page 106... ...
.2000. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol.
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From page 107... ...
1997. So carcinogens have thresholds: How do we decide what exposure levels should be considered safe?
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