Refinements to the Methods for Developing Spacecraft Exposure Guidelines (2016) / Chapter Skim
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2 Derivation of SMACs and SWEGs
2 Derivation of SMACs and SWEGs
Pages 14-40
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EVIDENCE IDENTIFICATION AND INTEGRATION The first step in developing SMACs and SWEGs is the conduct of a comprehensive literature search of both published and unpublished data from animal and human studies. Recent guidance on performing toxicologic assessments has called for more transparent documentation of how literature searches are performed, and suggests that a template be created to describe the search approach to ensure that relevant information is captured (NRC 2014)
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More targeted literature searches may be required to identify relevant supporting information. DERIVING SMACs AND SWEGs Different approaches have been used to establish exposure guidelines on the basis of whether the end point of concern is a cancer or a noncancer effect.
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or benchmark concentration (BMC) methods are now the preferred means for estimating a dose or concentration associated with a low level of excess health risk, generally in the risk range of 1-10%.
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For toxic effects other than cancer, the practice of risk assessment has been to estimate an acceptable exposure by dividing a no-observed-adverseeffect level (NOAEL) obtained from human studies or animal experiments by a set of uncertainty factors.
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should be consulted when using the benchmark dose approach for modeling quantal and continuous data sets. As needed, uncertainty factors are applied to obtain the final spacecraft exposure guideline.
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. Taste considerations are also addressed by the use of spaceflight-specific uncertainty factors (see section below on Spaceflight Factors)
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The dermal route of exposure plays a minor role in the uptake of airborne and waterborne contaminants in spacecraft and, therefore, except in the case of spills, is less important in setting exposure guidelines. The main portal of entry for air pollutants is via the respiratory tract.
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Exposure Adjustments Because studies will not be available on all of the exposure durations and routes of interest to NASA, it will be necessary for the agency to rely on the available data by making adjustments to account for the differences in exposure duration, exposure route, and species differences. Physiologically based pharmacokinetic models or dosimetry models can be used if adequate data are available (WHO 2010)
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Interspecies Adjustments If adequate data on a chemical's toxicokinetics and toxicodynamics are available, a PBPK model or chemical-specific adjustments can be used to calculate a human equivalent dose or concentration from animal data (e.g, see EPA 1994, 2002, 2011; WHO 2010)
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Both the nature of the toxicant and the duration of exposure are important considerations when deciding which uncertainty factors are relevant to deriving a particular exposure guideline. Interspecies Differences Inherent in the development of any toxicity guideline are the uncertainties related to variability in the toxic response among different species.
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Factors greater or less than 10 may also be used, depending on the nature of the toxicity. A factor of less than 10 may be applied if a human equivalent dose or concentration can be determined (e.g., from physiologically based pharmacokinetic models)
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SPACEFLIGHT FACTORS Spaceflight factors are uncertainty factors used by NASA to address effects of a chemical that are exacerbated by the physiological changes and stress
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The six effects for which spaceflight factors have been used by NASA include loss of bone mineral density, renal effects, cardiovascular effects, alterations in red-blood-cell mass, effects on immune response, and dehydration due to decreased water consumption. A spaceflight factor is used when there is evidence that a chemical could exacerbate one of these conditions.
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Daily sodium balance in microgravity is positive for greater sodium reabsorption in the kidney and lower excretion in the urine, and the retained sodium is transferred to extravascular spaces. Hypercalciuria from loss of bone mass may result in reduced water reabsorption by the kidney.
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. TABLE 2-1 Chemicals for which Spaceflight Factors Were Used to Derive SMACs or SWEGs Spaceflight Factor Chemicals Loss of bone mineral density Cadmium Renal effects Barium, chloroform, dichloroacetylene, methylene chloride, octamethyltrisiloxane, tert-butanol, trichloroethylene, ethylene glycol, and mercury Cardiovascular effects Barium, freon 11, freon 12, freon 21, and freon 113 Blood cells or volume Benzene, bromotrifluoromethane, di-n-butyl phthalate, unsymmetrical dimethylhydrazine, 2-ethoxyethanol, isoprene, indole, nitromethane, and trichloroethylene Immune response Nickel, 2-mercaptobenzothiazole Organoleptic effects C1-C4 mono-, di-, and tri-alkylamines, ammonia, antimony, barium, cadmium, dichloromethane, and silver
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(2008) studied the effects of spaceflight on renal stone formation by measuring urinary biomarkers of renal effects taken from 322 astronauts before and after short-duration flights on the Space Shuttle and comparing them with benchmark risk thresholds for the biomarkers.
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. Because the nature of the cardiovascular alterations can lead to serious effects on health, a spaceflight factor of 5 rather than 3 has been used by NASA.
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Astronauts also experience chronic stress and isolation, factors known to cause immune alterations. Rodent studies using spaceflight and microgravity models have reported impaired immune responses.
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. Thus, NASA uses evidence of reduced water consumption as a basis for setting SWEGs and also applies a spaceflight factor to reduce the potential for astronaut dehydration.
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In particular, fluid shifts in the body and space motion sickness may result in reduced food intake and nutritional status and reduced fluid consumption. In addition, loss of bone mass and muscle atrophy affect calcium and amino acid regulation, and astronauts reportedly land in a protein-depleted state (Stein and Schluter 2006)
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Whether an additional uncertainty factor should be considered in deriving spacecraft exposure guidelines for substances that affect the liver will depend on the specific mode of action of the chemical at low concentrations. In particular, substances that might exacerbate the effects of spaceflight on the liver potentially include those that produce oxidative stress or require phase I enzymes for detoxification, or those that might increase insulin resistance or affect insulin or blood sugar levels.
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For the literature searches, a template should be created to describe the search approach to ensure that relevant information is captured. At a minimum, NASA should specify the databases and sources that were searched, describe the search strategies for each database and source searched, and specify the dates of each search and the publication dates included.
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2014. Sensory irritation as a basis for setting occupational exposure limits.
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2015. The scientific basis of uncertainty factors used in setting occupational exposure limits.
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Pp. 273-292 in Principles of Clinical Medicine for Space Flight, M.R.
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2000. Methods for Developing Spacecraft Water Exposure Guidelines.
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2014. The Navigation Guide systematic review methodol ogy: A rigorous and transparent method for translating environmental health sci ence into better health outcomes.
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