Spacecraft water exposure guidelines for selected contaminants tủ tài liệu bách khoa

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C ommittee on Spacecraft Exposure Guidelines

Committee on Toxicology Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001

NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance

This project was supported by Contract No G-NAG 9-1451 between the National Academy of Sciences and the National Aeronautics and Space Administration Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project

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v

C OMMITTEE ON S PACECRAFT E XPOSURE G UIDELINES

Members

G AROLD S Y OST (Chair), University of Utah, Salt Lake City

A J OHN B AILER, Miami University, Oxford, OH

D AROL E D ODD, CIIT Centers for Health Research, Research Triangle Park,

NC

K EVIN E D RISCOLL, Procter and Gamble Pharmaceuticals, Mason, OH

D AVID G G AYLOR, Gaylor and Associates, Eureka Springs, AR1

J ACK R H ARKEMA, Michigan State University, East Lansing2

D AVID G K AUFMAN, University of North Carolina, Chapel Hill

K ENNETH R OSENMAN, Michigan State University, East Lansing

K ENNETH E T HUMMEL, University of Washington, Seattle

J OYCE T SUJI, Exponent Environmental Group, Inc., Bellevue, WA

R OCHELLE T YL, Research Triangle Institute, Research Triangle Park, NC

J UDITH T Z ELIKOFF, New York University School of Medicine, Tuxedo

Staff

J ENNIFER S AUNDERS, Project Director

E ILEEN N A BT, Senior Program Officer

S USAN N.J M ARTEL , Senior Program Officer

R UTH E C ROSSGROVE,Senior Editor

A LEXANDRA S TUPPLE, Senior Editorial Assistant

T AMARA D AWSON, Senior Program Assistant

Sponsor

N ATIONAL A ERONAUTICS AND S PACE A DMINISTRATION

1 David G Gaylor joined the committee in August 2005

2 Jack R Harkema joined the committee in October 2005.

C OMMITTEE ON T OXICOLOGY

Members

W ILLIAM E H ALPERIN (Chair), New Jersey Medical School, Newark

L AWRENCE S B ETTS, Eastern Virginia Medical School, Norfolk

E DWARD C B ISHOP, Parsons Corporation, Pasadena, CA

J AMES V B RUCKNER , University of Georgia, Athens

G ARY P C ARLSON, Purdue University, West Lafayette, IN

M ARION E HRICH, Virginia Tech, Blacksburg

S IDNEY G REEN, Howard University, Washington, DC

M ERYL K AROL , University of Pittsburgh, Pittsburgh

J AMES M C D OUGAL, Wright State University School of Medicine, Dayton, OH

R OGER M C I NTOSH, Science Applications International Corporation, Baltimore,

MD

G ERALD W OGAN , Massachusetts Institute of Technology, Cambridge

Staff

K ULBIR S B AKSHI, Program Director

E ILEEN N A BT, Senior Program Officer for Risk Analysis

S USAN N J M ARTEL, Senior Program Officer

E LLEN K M ANTUS , Senior Program Officer

J ENNIFER S AUNDERS, Associate Program Officer

A IDA N EEL, Program Associate

T AMARA D AWSON, Senior Program Assistant

R ADIAH R OSE, Senior Editorial Assistant

B OARD ON E NVIRONMENTAL S TUDIES AND T OXICOLOGY 3

Members

J ONATHAN M S AMET (Chair), Johns Hopkins University, Baltimore, MD

R AMO ҁ N A LVAREZ, Environmental Defense, Austin, TX

J OHN M B ALBUS,Environmental Defense, Washington, DC

D ALLAS B URTRAW,Resources for the Future, Washington, DC

J AMES S B US,Dow Chemical Company, Midland, MI

C OSTEL D D ENSON,University of Delaware, Newark

E D ONALD E LLIOTT,Willkie Farr & Gallagher LLP, Washington, DC

M ARY R E NGLISH , University of Tennessee, Knoxville

J P AUL G ILMAN, Oak Ridge Center for Advanced Studies, Oak Ridge, TN

S HERRI W G OODMAN, Center for Naval Analyses, Alexandria, VA

J UDITH A G RAHAM, American Chemistry Council, Arlington, VA

W ILLIAM P H ORN,Birch, Horton, Bittner and Cherot, Washington, DC

J AMES H J OHNSON , J R ,Howard University, Washington, DC

W ILLIAM M L EWIS , J R , University of Colorado, Boulder

J UDITH L M EYER,University of Georgia, Athens

D ENNIS D M URPHY , University of Nevada, Reno

P ATRICK Y O’B RIEN, ChevronTexaco Energy Technology Company,

Richmond, CA

D OROTHY E P ATTON (retired), Chicago, IL

D ANNY D R EIBLE , University of Texas, Austin

J OSEPH V R ODRICKS, ENVIRON International Corporation, Arlington, VA

A RMISTEAD G R USSELL,Georgia Institute of Technology, Atlanta

R OBERT F S AWYER,University of California, Berkeley

L ISA S PEER, Natural Resources Defense Council, New York, NY

K IMBERLY M T HOMPSON, Massachusetts Institute of Technology, Cambridge

M ONICA G T URNER,University of Wisconsin, Madison

M ARK J U TELL,University of Rochester Medical Center, Rochester, NY

C HRIS G W HIPPLE,ENVIRON International Corporation, Emeryville, CA

L AUREN Z EISE, California Environmental Protection Agency, Oakland

Senior Staff

J AMES J R EISA, Director

D AVID J P OLICANSKY, Scholar

R AYMOND A W ASSEL, Senior Program Officer for Environmental Sciences and

Engineering

K ULBIR B AKSHI, SeniorProgram Officer for Toxicology

E ILEEN N A BT,Senior Program Officer for Risk Analysis

3 This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology

K ARL E G USTAVSON,Senior Program Officer

K J OHN H OLMES, Senior Program Officer

E LLEN K M ANTUS, Senior Program Officer

S USAN N.J M ARTEL, Senior Program Officer

S TEVEN K G IBB,Program Officer for Strategic Communications

R UTH E C ROSSGROVE, Senior Editor

ix

O THER R EPORTS OF THE

B OARD ON E NVIRONMENTAL S TUDIES AND T OXICOLOGY

Scientific Review of the Proposed Risk Assessment Bulletin from the Office of Management and Budget (2007)

Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues (2006)

New Source Review for Stationary Sources of Air Pollution (2006) Human Biomonitoring for Environmental Chemicals (2006) Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment (2006)

Fluoride in Drinking Water: A Scientific Review of EPA’s Standards (2006) State and Federal Standards for Mobile-Source Emissions (2006)

Superfund and Mining Megasites—Lessons from the Coeur d’Alene River Basin (2005)

Health Implications of Perchlorate Ingestion (2005) Air Quality Management in the United States (2004) Endangered and Threatened Species of the Platte River (2004) Atlantic Salmon in Maine (2004)

Endangered and Threatened Fishes in the Klamath River Basin (2004) Cumulative Environmental Effects of Alaska North Slope Oil and Gas Development (2003)

Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002)

Biosolids Applied to Land: Advancing Standards and Practices (2002) The Airliner Cabin Environment and Health of Passengers and Crew (2002) Arsenic in Drinking Water: 2001 Update (2001)

Evaluating Vehicle Emissions Inspection and Maintenance Programs (2001) Compensating for Wetland Losses Under the Clean Water Act (2001)

A Risk-Management Strategy for PCB-Contaminated Sediments (2001) Acute Exposure Guideline Levels for Selected Airborne Chemicals (five volumes, 2000-2006)

Toxicological Effects of Methylmercury (2000) Strengthening Science at the U.S Environmental Protection Agency (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) Ecological Indicators for the Nation (2000)

Waste Incineration and Public Health (1999) Hormonally Active Agents in the Environment (1999) Research Priorities for Airborne Particulate Matter (four volumes, 1998-2004) The National Research Council’s Committee on Toxicology: The First 50 Years (1997)

Carcinogens and Anticarcinogens in the Human Diet (1996) Upstream: Salmon and Society in the Pacific Northwest (1996) Science and the Endangered Species Act (1995)

Wetlands: Characteristics and Boundaries (1995)

Biologic Markers (five volumes, 1989-1995) Review of EPA’s Environmental Monitoring and Assessment Program (three volumes, 1994-1995)

Science and Judgment in Risk Assessment (1994) Pesticides in the Diets of Infants and Children (1993) Dolphins and the Tuna Industry (1992)

Science and the National Parks (1992) Human Exposure Assessment for Airborne Pollutants (1991) Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991) Decline of the Sea Turtles (1990)

Copies of these reports may be ordered from the National Academies Press

(800) 624-6242 or (202) 334-3313

www.nap.edu

xi

O THER R EPORTS OF THE C OMMITTEE ON T OXICOLOGY

Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents (2005)

Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, Volume 1 (2004)

Spacecraft Water Exposure Guidelines for Selected Contaminants, Volume 1 (2004)

Toxicologic Assessment of Jet-Propulsion Fuel 8 (2003) Review of Submarine Escape Action Levels for Selected Chemicals (2002) Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (2001)

Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity (2001)

Acute Exposure Guideline Levels for Selected Airborne Contaminants, Volume

1 (2000), Volume 2 (2002), Volume 3 (2003), Volume 4 (2004), Volume

5 (2007) Review of the US Navy’s Human Health Risk Assessment of the Naval Air Facility at Atsugi, Japan (2000)

Methods for Developing Spacecraft Water Exposure Guidelines (2000) Review of the U.S Navy Environmental Health Center’s Health-Hazard Assessment Process (2000)

Review of the U.S Navy’s Exposure Standard for Manufactured Vitreous Fibers (2000)

Re-Evaluation of Drinking-Water Guidelines for Diisopropyl Methylphosphonate (2000)

Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: 236fa, HFC-23, and HFC-404a (2000)

HFC-Review of the U.S Army’s Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents (1999)

Toxicity of Military Smokes and Obscurants, Volume 1 (1997), Volume 2 (1999), Volume 3 (1999)

Assessment of Exposure-Response Functions for Rocket-Emission Toxicants (1998)

Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 (1996)

Permissible Exposure Levels for Selected Military Fuel Vapors (1996) Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 1 (1994), Volume 2 (1996), Volume 3 (1996), Volume 4 (2000)

xiii

Preface

The National Aeronautics and Space Administration (NASA) maintains an active interest in the environmental conditions associated with living and work-ing in spacecraft and identifying hazards that might adversely affect the health and well-being of crew members Despite major engineering advances in con-trolling the spacecraft environment, some water and air contamination is inevi-table Several hundred chemical species are likely to be found in the closed envi-ronment of the spacecraft, and as the frequency, complexity, and duration of human space flight increase, identifying and understanding significant health hazards will become more complicated and more critical for the success of the missions

NASA asked the National Research Council (NRC) Committee on cology to develop guidelines, similar to those developed by the NRC in 1992 for airborne substances, for examining the likelihood of adverse effects from water contaminants on the health and performance of spacecraft crews In 2000, the

Toxi-NRC report Methods for Developing Spacecraft Water Exposure Guidelines was

published, and NASA now uses those methods for developing spacecraft water exposure guidelines (SWEGs) for individual water contaminants NASA is re-sponsible for selecting the water contaminants for which SWEGs will be estab-lished To ensure that the SWEGs are developed in accordance with the NRC guidelines, NASA requested that the NRC committee independently review the draft SWEG documents In its evaluations, the committee reviews the docu-ments as many times as necessary until it is satisfied that the SWEGs are scien-

tifically justified This report is the second volume in the series, Spacecraft

Wa-ter Exposure Guidelines for Selected Contaminants Spacecraft WaWa-ter Exposure Guidelines Volume 1, published in 2004, used the NASA guidelines to establish

exposure concentrations for phenol, N-phenyl-beta-naphthylamine, methane, chloroform, di(2-ethylhexyl) phthalate, di-n-butyl phthalate, silver, and

dichloro-2-mercaptobenzothiazole This second volume presents SWEGs for acetone,

to the study charge The review comments and draft manuscript remain dential to protect the integrity of the deliberative process We wish to thank the following individuals for their review of this report: James V Bruckner, Uni-versity of Georgia; Barbara Callahan, University Research Engineers and Asso-ciates; Samuel Kacew, University of Ottawa; John O’Donoghue, University of Rochester, School of Medicine and Denistry; and Robert Young, Oak Ridge National Laboratory

confi-Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release The review of this report was overseen by Ernest McConnell, ToxPath, Inc Appointed by the NRC, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered Responsibility for the final content of this report rests entirely with the authoring committee and the institution

Special thanks are extended to John James and Torin McCoy (NASA); Hector Garcia and Raghupathy Ramanathan (Wyle Laboratories); and Jean Hampton (Texas Southern University) for preparing and revising the SWEG documents We would also like to thank previous members of the committee who contributed to the development of this document including Joseph Brady, The Johns Hopkins University; Gary Carlson, Purdue University; Donald Gard-ner, Inhalation Toxicology Associates; Elaine Faustman, University of Washing-ton; Charles E Feigley, University of South Carolina; Mary Esther Gaulden, The University of Texas Southwestern Medical Center at Dallas; William Halperin, New Jersey Medical School; Ralph Kodell, Food and Drug Admini-stration; Robert Snyder, Rutgers, The State University of New Jersey; Bernard Wagner, Independent Consultant; and Bernard Weiss, University of Rochester School of Medicine and Dentistry

We are grateful for the assistance of the NRC staff in supporting this ject and preparing the report Staff members who contributed to this effort are James J Reisa, director of the Board on Environmental Studies and Toxicology and Alexandra Stupple, senior editorial assistant We especially wish to recog-nize the contributions of senior program officers, Eileen Abt and Susan N.J

xvii

Contents

I NTRODUCTION 1

A PPENDIXES 1 ACETONE 11

2 AMMONIA 39

3 BARIUM AND BARIUM SALTS 52

4 C1-C4MONO-,DI-, AND TRIALKYLAMINES 96

5 CADMIUM (INORGANIC SALTS) 154

6 CAPROLACTAM 264

7 FORMALDEHYDE 300

8 FORMATE 342

9 MANGANESE (INORGANIC SALTS) 364

10 TOTAL ORGANIC CARBON 453

11 ZINC AND ZINC SALTS (INORGANIC) 465

1

Introduction

Construction of the International Space Station (ISS)—a tional effort—began in 1999 In its present configuration, the ISS is ex-pected to carry a crew of three to six astronauts for up to 180 days (d) Because the space station will be a closed and complex environment, some contamination of its internal atmosphere and water system is un-avoidable Several hundred chemical contaminants are likely to be found

multina-in the closed-loop atmosphere and recycled water of the space station

To protect space crews from contaminants in potable and hygiene water, the National Aeronautics and Space Administration (NASA) re-quested that the National Research Council (NRC) provide guidance on how to develop water exposure guidelines and subsequently review NASA’s development of the exposure guidelines for specific chemicals The exposure guidelines are to be similar to those established by the NRC for airborne contaminants (NRC 1992; 1994; 1996a,b; 2000a) The NRC was asked to consider only chemical contaminants, and not micro-bial agents The NRC convened the Committee on Spacecraft Water Ex-posure Guidelines to address this task The Committee published its first report Methods for Developing Spacecraft Water Exposure Guidelines in

2000 A second report, Spacecraft Water Exposure Guidelines for lected Contaminants, Volume 1 (2004a), used these guidelines to set ex-

Se-posure levels for nine chemicals: chloroform, dichloromethane,

di-n-butyl phthalate, di(2-ethylhexyl) phthalate, 2-mercaptobenzothiazole, nickel, phenol, N-phenyl-beta-napthylamine, and silver

Spacecraft water exposure guidelines (SWEGs) are to be lished for exposures of 1, 10, 100, and 1,000 d The 1-d SWEG is a con-centration of a substance in water that is judged to be acceptable for the performance of specific tasks during rare emergency conditions lasting

estab-2 Spacecraft Water Exposure Guidelines

for periods up to 24 hours (h) The 1-d SWEG is intended to prevent reversible harm and degradation in crew performance Temporary dis-comfort is permissible provided there is no effect on judgment, perform-ance, or ability to respond to an emergency Longer-term SWEGs are intended to prevent adverse health effects (either immediate or delayed) and degradation in crew performance that could result from continuous exposure in closed spacecraft for as long as 1,000 d In contrast with the 1-d SWEG, longer-term SWEGs are intended to provide guidance for exposure under the expected normal operating conditions in spacecraft

ir-WATER CONTAMINANTS

Water used in NASA’s space missions must be carried from Earth

or generated by fuel cells The water is used for drinking, food tution, oral hygiene, hygienic uses (handwashing, showers, urine flush-ing), and oxygen generation Because of plans for longer spaceflights and habitation of the ISS, water reclamation, treatment, and recycling is re-quired Water for long spaceflights can be reclaimed from several on-board sources, including humidity condensate from the cabin, hygiene water (shower and wash water), and urine Each of those sources will have a variety of contaminants Humidity condensate will have contami-nants released into the cabin from crew activities (for example, by-products of crew metabolism, food preparation, and hygiene activities) from routine operation of the air-revitalization system, from off-gassing

reconsti-of materials and hardware, from payload experiments, and from routine in-flight use of the crew health care system Wash water will include de-tergents and other personal hygiene products Urine contains electrolytes, small-molecular-weight proteins, and metabolites of nutrients and drugs

It is chemically treated and distilled before recycling, which causes a variety of by-products to be formed Other sources of chemical contami-nants include mechanical leaks, microbial metabolites, payload chemi-cals, biocidal agents added to the water to retard bacterial growth (such

as silver and iodine), fouling of the filtration system, and incomplete processing of the water

It is also possible that contaminants in the spacecraft atmosphere will end up as toxic substances in the water system The air and water systems of the ISS constitute a single life-support system, and the use of condensate from inside the cabin as a source of drinking water could in-troduce some unwanted substances into the water system

Introduction 3

SUMMARY OF THE REPORT

ON METHODS FOR DEVELOPING SWEGs

Data

In developing SWEGs, several types of data should be evaluated, including data on (1) the physical and chemical characteristics of the contaminant, (2) in vitro toxicity studies, (3) toxicokinetic studies, (4) animal toxicity studies conducted over a range of exposure durations, (5) genotoxicity studies, (6) carcinogenicity bioassays, (7) human clinical and epidemiology studies, and (8) mechanistic studies All observed toxic effects should be considered, including mortality, morbidity, func-tional impairment, specific organ system toxicities (such as renal, he-patic, and endocrine), neurotoxicity, immunotoxicity, reproductive toxic-ity, genotoxicity, and carcinogenicity Taste and odor thresholds are also relevant end points for setting SWEGs

Data from oral exposure studies should be used—particularly ing water and feed studies in which the duration of exposure approxi-mates anticipated human exposure times Gavage studies can also be used, but they should be interpreted carefully because they involve the bolus administration of a substance directly to the stomach within a brief period of time Such exposure could result in blood concentrations of contaminants and attendant effects that might not be observed if the ad-ministration were spread out over several smaller doses, as would be ex-pected with the normal pattern of water consumption Dermal absorption and inhalation studies should also be evaluated, because exposure from those routes occur when water is used for hygiene purposes

drink-There are several important determinants for deriving a SWEG, including identifying the most sensitive target organ or body system af-fected; the nature of the effect on the target tissue; dose-response rela-tionships for the target tissue; the rate of recovery; the nature and sever-ity of the injury; cumulative effects; toxicokinetic data; interactions with other chemicals; and the effects of microgravity

Risk Assessment

There are several risk assessment methods that can be used to rive SWEGs Risk assessments for exposure to noncarcinogenic sub-stances traditionally have been based on the premise that an adverse

de-4 Spacecraft Water Exposure Guidelines

health effect will not occur below a specific threshold exposure Given this assumption, an exposure guidance level can be established by divid-ing the no-observed-adverse-effect level (NOAEL) or the lowest-observed-adverse-effect level (LOAEL) by an appropriate set of uncer-tainty factors This method requires making judgements about the critical toxicity end point relevant to a human in space, the appropriate study for selecting a NOAEL or LOAEL, and the magnitudes of the uncertainty factors used in the process

For carcinogenic effects known to result from direct mutagenic events, no threshold dose would be assumed However, when carcino-genesis results from nongenotoxic mechanisms, a threshold dose can be considered Estimation of carcinogenic risk involves fitting mathematical models to experimental data and extrapolating to predict risks at doses that are usually well below the experimental range The multistage model

of Armitage and Doll (1960) is used most frequently for low-dose trapolation According to multistage theory, a malignant cancer cell de-velops from a single stem cell as a result of several biologic events (for example, mutations) that must occur in a specific order There also is a two-stage model that explicitly provides for tissue growth and cell kinet-ics

ex-An alternative to the traditional NOAEL and LOAEL risk ment methods that are used to set carcinogenic and noncarcinogenic con-centrations is the benchmark dose (BMD) approach The BMD is the dose associated with a specified low level of excess health risk, generally

assess-in the risk range of 1-10% (BMDL01 and BMDL10), that can be estimated from modeled data with little or no extrapolation outside the experimen-tal dose range The BMDL01 and BMDL10 are defined as the statistical lower confidence limits of doses that correspond to excess risks of 1% and 10% above background concentrations, respectively Use of the lower confidence limit provides a suitable method to incorporate experi-mental uncertainty However, the use of a central estimate of the bench-mark dose, with incorporation of an additional uncertainty factor to ac-count for experimental variation, may be more appropriate for certain kinds of data Like the NOAEL and LOAEL, the BMDL01 and BMDL10are points of departure for establishing exposure guidelines and should

be modified by appropriate exposure conversions and uncertainty factors Scientific judgment is often a critical, overriding factor in applying the methods described above It is recommended that when sufficient dose-response data are available, the BMD approach be used to calculate exposure guidelines However, in the absence of sufficient data, or when

Introduction 5

special circumstances dictate, the other, more traditional approaches should be used

Special Considerations for NASA

When deriving SWEGs, either by the traditional or BMD approach,

it will be necessary to use exposure conversions and uncertainty factors

to adjust for weaknesses or uncertainties about the data When adequate data are available, exposure conversions that NASA should use include those to adjust for target tissue dose, differences in exposure duration, species differences, and differences in routes of exposure.1 Uncertainty factors should also be used to extrapolate animal exposure data to hu-mans, when human exposure data are unavailable or inadequate; to ex-trapolate data from subchronic studies to chronic exposure; to account for using BMDL10 instead of BMDL01 (or a LOAEL instead of a NOAEL); to account for experimental variation; and to adjust for space-flight factors that could alter the toxicity of water contaminants The lat-ter factors are used to account for uncertainties associated with micro-gravity, radiation, and stress Some of the ways astronauts can be physi-cally, physiologically, and psychologically compromised include de-creased muscle mass, decreased bone mass, decreased red blood cell mass, depressed immune systems, altered nutritional requirements, be-havioral changes, shift of body fluids, altered blood flow, altered hormo-nal status, altered enzyme concentrations, increased sensitization to car-diac arrhythmias, and altered drug metabolism There is generally little information to permit a quantitative conversion that would reflect altered toxicity resulting from spaceflight environmental factors Thus, space-flight uncertainty factors should be used when available information on a substance indicates that it could compound one or more aspects of an astronaut’s condition that might already be compromised in space

Another commonly used uncertainty factor is one that accounts for variable susceptibilities in the human population That uncertainty factor

is used to protect sensitive members of the general population, including young children, pregnant women, and the immune compromised Be-cause the astronaut population is typically composed of healthy nonpreg-

1Two liters per day was used as the default for drinking water consumption, though this quantity may not be applicable in all situations

al-6 Spacecraft Water Exposure Guidelines

nant adults, the committee believes that an uncertainty factor for pecies differences should only be used if there is evidence that some in-dividuals could be especially susceptible to the contaminant These dif-ferences could be observed among astronauts who possess genetic poly-morphisms for well-established genes

intras-Exposure Guidelines Set by Other Organizations

Several regulatory agencies have established exposure guidance levels for some of the contaminants of concern to NASA Those guid-ance levels should be reviewed before SWEGs are established The pur-pose of this comparison would not be simply to mimic the regulatory guidelines set elsewhere, but to determine how and why other exposure guidelines might differ from those of NASA and to assess whether those differences are reasonable in light of NASA’s special needs

REVIEW OF SWEG REPORTS

NASA is responsible for selecting the water contaminants for which SWEGs will be established and for developing documentation on how SWEG values were determined As described above, the procedure for developing SWEGs involves identifying toxicity effects relevant to astronauts and calculating exposure concentrations on the basis of those end points The lowest exposure concentration is selected as the SWEG, because the lowest value would be expected to protect astronauts from manifesting other effects as well

To ensure that the SWEGs are developed in accordance with the NRC guidelines (2000b), NASA requested that the NRC committee in-dependently review NASA’s draft SWEGs documents NASA’s draft documents summarize data relevant to assessing risk from exposure to individual contaminants in water only; they are not comprehensive re-views of the available literature on specific contaminants Furthermore, although the committee is mindful that contaminants will be present as mixtures in drinking water and the potential exists for interactions, the committee was asked to consider each chemical on an individual basis The committee reviews NASA’s SWEG documents and provides com-ments and recommendations in a series of interim reports (see NRC 2000c,d,e; 2001; 2002; 2003; 2004b,c; 2005) The committee reviews

of the toxicity data cited in the SWEG reports

This report is the second volume in the series Spacecraft Water posure Guidelines for Selected Chemicals SWEG reports for acetone, alkylamines, ammonia, barium, cadmium, caprolactam, formate, formal-dehyde, manganese, total organic carbon, and zinc are included in the appendix of this report The committee concludes that the SWEGs de-veloped in those documents are scientifically valid values based on the data reviewed by NASA and are consistent with the NRC (2000b) guide-line report SWEG reports for additional chemicals will be presented in subsequent volumes

Ex-REFERENCES

Armitage, P., and R Doll 1960 Stochastic models for carcinogenesis Pp

19-38 in Proceedings of the Fourth Berkeley Symposium on Mathematical Statistics and Probability, J Neyman, ed Berkeley, CA: University of California Press

NRC (National Research Council) 1992 Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants Washington, DC: National Academy Press

NRC (National Research Council) 1994 Spacecraft Maximum Allowable centrations for Selected Airborne Contaminants, Volume 1 Washington, DC: National Academy Press

Con-NRC (National Research Council) 1996a Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 2 Washing-ton, DC: National Academy Press

NRC (National Research Council) 1996b Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 3 Washing-ton, DC: National Academy Press

NRC (National Research Council) 2000a Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 4 Washing-ton, DC: National Academy Press

NRC (National Research Council) 2000b Methods for Developing Spacecraft Water Exposure Guidelines Washington, DC: National Academy Press NRC (National Research Council) 2000c Letter Report 2 on Spacecraft Water Exposure Guidelines Washington, DC: National Academy Press

8 Spacecraft Water Exposure Guidelines

NRC (National Research Council) 2000d Interim Report 3 on Spacecraft Water Exposure Guidelines Washington, DC: National Academy Press

NRC (National Research Council) 2000e Interim Report 4 on Spacecraft Water Exposure Guidelines Washington, DC: National Academy Press

NRC (National Research Council) 2001 Interim Report 5 on Spacecraft Water Exposure Guidelines Washington, DC: National Academy Press

NRC (National Research Council) 2002 Interim Report 6 on Spacecraft Water Exposure Guidelines Washington, DC: The National Academies Press NRC (National Research Council) 2003 Interim Report 7 on Spacecraft Water Exposure Guidelines Washington, DC: The National Academies Press NRC (National Research Council) 2004a Spacecraft Water Exposure Guide-lines for Selected Contaminants Volume 1 Washington, DC: The Na-tional Academies Press

NRC (National Research Council) 2004b Interim Report 8 on Spacecraft Water Exposure Guidelines Washington, DC: The National Academies Press NRC (National Research Council) 2004c Interim Report 9 on Spacecraft Expo-sure Guidelines Washington, DC: The National Academies Press

NRC (National Research Council) 2005 Interim Report 10 on Spacecraft sure Guidelines Washington, DC: The National Academies Press

Expo-Appendixes

11

1 Acetone

Hector D Garcia, Ph.D NASA-Johnson Space Center Toxicology Group Habitability and Environmental Factors Branch

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Acetone is a clear, colorless, highly volatile, flammable liquid with

a sweet, fruity aroma (odor threshold = 13 parts per million [ppm]) and excellent solvent properties It forms explosive mixtures with air or oxy-gen (see Table 1-1)

OCCURRENCE AND USE

Acetone is a product of normal metabolism in humans and animals

It is produced during the breakdown of fat and is used in the synthesis of glucose and fat Trace amounts are detectable in normal human blood (7.0-14.0 micromoles per liter [μmol/L] = 0.4-0.8 micrograms per millili-ter [μg/mL]) and urine (4.0-35.0 μmol/L = 0.2-2.0 μg/mL) (Rowe and Wolf 1963; Wang et al 1994; de Oliveira and Pereira Bastos de Siqueira 2004) Endogenous concentrations of acetone in the blood have been re-ported up to 10 μg/mL, and concentrations during diabetic ketoacidosis have ranged from 100 to 700 μg/mL (Gamis and Wasserman 1988) Data from a National Institute for Occupational Safety and Health (NIOSH) report (Stewart et al 1975) on acetone suggest that normal blood acetone concentrations in women (1.8-4.2 mg% = 18-42 μg/dL) may be two to three times higher than in men (0.5-1.4 mg% = 5-14 μg/mL), but no other reports could be found to confirm this High acetone concentrations

in serum and breath are often indicative of altered metabolic states cluding diabetes, vitamin E deficiency, and fasting (NTP 1991)

in-12 Spacecraft Water Exposure Guidelines

TABLE 1-1 Physical and Chemical Properties of Acetonea

Formula C3H6O

dimethyl formaldehyde, dimethylketal, ketone propane, beta-ketopropane, methyl ketone, pyroacetic acid, pyroacetic ether

Solubility Infinitely soluble in water; miscible with

alcohol, dimethylformamide, chloroform, most oils, and ether

Lower Explosive Limit 2% (in air) Upper explosive Limit 13% (in air) Odor Threshold (in air) 13 ppm; 47 mg/m3 Odor Threshold (in water) 20 ppm; 20 mg/L

aData from HSDB 2006

Acetone is not routinely used in spacecraft during flight but may be part of in-flight scientific experiments Acetone is found in the spacecraft atmosphere on almost every mission at concentrations up to 8 ppm in Skylab (Liebich et al 1975) and up to 1.2 ppm during shorter Shuttle missions—probably from crew metabolism and offgassing

TOXICOKINETICS AND METABOLISM

Much of the data in the literature regarding acetone toxicokinetics and metabolism involves exposure by inhalation, but because of the gen-eral distribution of acetone in body water and its relatively slow metabo-lism, as described below, the data should hold true for acetone exposures

Acetone 13

degree, through the skin The rate of absorption of ingested acetone pends on the amount of food in the stomach In one subject, peak blood levels of acetone were seen 10 min after ingestion of acetone on an empty stomach, while acetone ingested about 10 min after a meal was more slowly absorbed, with lower peak levels achieved at 48-59 min af-ter ingestion (Widmark 1919)

de-Distribution

No studies were found on the distribution of acetone after ingestion

In studies of the inhalation toxicokinetics of acetone in rats, Hallier

et al (1981) found that acetone is mainly, but not exclusively, distributed within the body water compartment under conditions of negligible me-tabolism (saturation of metabolizing enzymes) The kinetics of the exha-lation of acetone was strictly monoexponential, indicating that it does not distribute into a “deep compartment”—that is, one from which it is re-leased only slowly Also, acetone is water soluble and will not accumu-late in adipose tissue

Mice exposed to 2-[14C]-acetone vapor (500 ppm) for periods of 1 h

to 5 days (d) were examined for the tissue distribution of radioactivity (Löf et al 1980; Wigaeus et al 1982) The amount of radioactivity in tissues increased as the exposure time increased from 1 to 6 h but in-creased only slightly or not at all in all tissues except adipose tissue at exposure times greater than 6 h (12 h, 24 h, and 5 d) (Wigaeus et al

1982) Liver and pancreas showed the highest concentration of tivity; the lowest concentrations were in muscles and white adipose tis-sue After 3 or 5 d of inhalation exposure (6 h/d) to 500 ppm 2-[14C]-acetone vapor, the radioactive concentration in mouse tissues was highest

radioac-in brown adipose tissue, followed by liver and pancreas (Wigaeus et al

1982) Only about 10% of the radioactivity in the liver was unchanged acetone

Metabolism

Ramu et al (1978) in a case report involving the ingestion of nail polish remover by an alcoholic estimated that humans can metabolize acetone at a rate probably not exceeding 1 g/h, but none of the metabo-lites were identified On a gram per kilogram basis, the rate of acetone metabolism in humans has been reported to be about half that the rat

14 Spacecraft Water Exposure Guidelines

(Haggard et al 1944), with metabolism being nonlinear and saturable Haggard et al documented a zero-order elimination rate in rats of 13 mil-ligrams per kilograms per hour (mg/kg/h) at a blood acetone concentra-tion of 0.2 g/deciliter (dL) In a 10-d study of female rats, tolerance was reported to develop whereby the effects of inhaled acetone on the inhibi-tion of avoidance behavior and escape response in rats became weaker upon repeated administration (Goldberg et al 1964), probably because of

an induction of metabolic enzymes in the liver

Several studies in rats have shown that acetone can be metabolized

by three separate gluconeogenic pathways, with the first step in all cases being the hydroxylation of one of the methyl groups by acetone mono-oxygenase to form acetol (NTP 1991) One of the intermediates in the metabolism of acetone to carbon dioxide is formate, which in humans, is metabolized more slowly than in rodents

Elimination

The main route of excretion of acetone is via the lungs—regardless

of the route of exposure—with very little excreted in the urine (Ramu et

al 1978; Wigaeus et al 1981; Gamis and Wasserman 1988) About half

of the acetone is exhaled unchanged in humans, and the other half is haled as carbon dioxide produced from the metabolism of acetone (Wi-gaeus et al 1982) Several different estimates of the half-life of acetone

ex-in blood have been reported, with the reported half-life ex-increasex-ing with the dose of acetone (DiVincenzo et al 1973; Ramu et al 1978; Wigaeus

et al 1981; Gamis and Wasserman 1988) In acute intoxications in adult humans, the half-life of acetone in plasma has been estimated at ap-proximately 31 h and is consistent with a first-order elimination process (Ramu et al 1978) A more recent estimate of the elimination plasma half-life of acetone in humans is 18 h (Sakata et al 1989) Jones reported half-lives for acetone in the blood and urine ranging from 3-27 h, but some of the measurements were from ingestion of isopropanol or dena-tured alcohol rather than acetone itself (Jones 2000) A half-life of only 3.9 h was estimated for volunteers inhaling acetone at 250 ppm for 4-h and assuming first-order kinetics (Dick et al 1988) A case report of a 42-year-old man who intentionally swallowed 800 mL of acetone re-ported acetone concentrations of 2,000 mg/L in serum and 2,300 mg/L in urine and an elimination half-life of 11 h with sequelae-free survival af-ter aggressive treatments including multiple gastric lavages, hyperventi-lation, hemofiltration, forced diuresis and hydration (Zettinig et al

Acetone 15

1997) Two studies on inhaled acetone (Matsushita et al 1969b and Vincenzo et al 1973, as cited in OSHA 1989) suggest that chronic in-termittent exposure to high enough doses of acetone on a daily basis can lead to the bioaccumulation of acetone Based on Ramu et al.’s (1978) estimate of the maximum metabolism rate in humans (1 g/h), accumula-tion in the blood should be seen for dose rates exceeding about 24 g/d

Di-On a milligram per kilogram basis, Haggard et al.’s (1944) estimate of the metabolic rate of acetone in rats implies that dose rates exceeding about 11 g/d in humans could lead to an accumulation of acetone in a 70-

al 1978; Gamis and Wasserman 1988) Other adverse effects of high doses include vomiting, hematemesis, excessive thirst, polyuria, hyper-glycemia, and occasionally, metabolic acidosis (probably because of the metabolism of acetone to formate) (Ross 1973; Ramu et al 1978; Gamis and Wasserman 1988) One Soviet investigator reported that four indi-viduals acutely exposed (one by inhalation and three orally) to unspeci-fied concentrations and amounts of acetone developed liver lesions and,

in two of the orally intoxicated individuals, mild renal lesions (Mirchev 1977) The quality of this case study report was not evaluated, because it was written in Bulgarian with only the abstract translated into English;

thus, it could not be determined if the four patients had also been posed to other agents such as alcohol or may have had pre-existing le-sions of the liver or kidneys

ex-Acute and Short-Term Exposures General

Humans who ingest up to 20 mL of acetone do not show any verse effects (Gosselin et al 1984) Ingestion of 200 mL, however, can