Current Intelligence Bulletin 60

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Current Intelligence Bulletin 60

Interim Guidance for Medical Screening andHazard Surveillance for Workers Potentially

Exposed to Engineered Nanoparticles

DEPARTMENT OF HEALTH AND HUMAN SERVICESCenters or Disease Control and Prevention

National Institute or Occupational Saety and Health


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This document is in the public domain and may be freely copied or

reprinted.

Disclaimer

Mention o any company or product does not constitute endorsement by the Na-tional Institute or Occupational Saety and Health (NIOSH). In addition, citationsto Web sites external to NIOSH do not constitute NIOSH endorsement o the spon-soring organizations or their programs or products. Furthermore, NIOSH is notresponsible or the content o these Web sites. All Web addresses reerenced in thisdocument were accessible as o the publication date.

Ordering Informationo receive documents or other inormation about occupational saety and healthtopics, contact NIOSH at

elephone: 1800CDCINFO (18002324636)Y: 18882326348E-mail: [email protected]

or visit the NIOSH Web site at www.cdc.gov/niosh.

For a monthly update on news at NIOSH, subscribe to NIOSH eNewsby visitingwww.cdc.gov/niosh/eNews.

DHHS (NIOSH) Publication No. 2009116

February 2009

Safer Healthier PeopleTM


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NIOSH will also continue to consider the strengths and weaknesses o establishingexposure registries or workers potentially exposed to engineered nanoparticles oruture health surveillance and epidemiological studies.


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ContentsForeword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii

Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Background: Brie Review o the Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Effects o Exposure to Ultrafine Particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Effects o Exposure to Engineered Nanoparticles . . . . . . . . . . . . . . . . . . . . . . 2

Occupational Health Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Medical Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Frequent Uses or Medical Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Hazard Surveillance and Risk Management . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Discussion and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

ake Prudent Measures to Control Exposures toEngineered Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Conduct Hazard Surveillance as the Basis or Implementing Controls . . . . 7

Continue use o Established Medical Surveillance Approaches . . . . . . . . . . 7Reerences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Appendix A:Critical Aspects o an Occupational Medical ScreeningProgram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Appendix B: OSHA Standards Tat Include Requirements orMedical Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Appendix C: Hazards or Which NIOSH Has Recommended the Use oMedical Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Appendix D: Discussion o Occupational Health Surveillance Programswith Medical Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Appendix E: Examples o Limitations in the Evidence Base or SpecificMedical Screening o Workers Exposed to Engineered Nanoparticles . . . . . . 21

Single-Walled Carbon Nanotubes (SWCNs) . . . . . . . . . . . . . . . . . . . . . . . . . 21

Nanoscale Metal Oxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Nanoscale Cadmium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Appendix F: Exposure Registries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23


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AcknowledgementsTis Current Intelligence Bulletin (CIB) was developed by the staff o the Nation-al Institute or Occupational Saety and Health (NIOSH) who participate in theNIOSH Nanotechnology Research Center (NRC). Special thanks go to Paul S.Schulte, Director, Education and Inormation Division, NIOSH and manager o theNRC, Douglas rout, and Ralph D. Zumwalde or writing and organizing the re-port. Te NIOSH NRC also acknowledges the contributions o Vanessa Becks andGino Fazio or desktop publishing and graphic design, and Douglas Platt or editingthe document.

NIOSH greatly appreciates the time and efforts o expert peer reviewers and NRCstaff who provided comments on a draf o this CIB.

Peer Reviewers

Michael Kosnett, MD, MPHUniversity o Colorado at Denver and Health Sciences Center

Ken Donaldson, BSc, PhD, DSc, CBiol, FRCPath, FFOMUniversity o Edinburgh Centre or Inflammation Research, ELEGI ColtLaboratory

James Lockey, MD, Proessor o Occupational, Environmental and PulmonaryMedicine, University o Cincinnati

Attendees and Participants: Workshop on occupational health surveillance

and nanotechnology workers. April 1718, 2007, Arlington, VA.

Richard CanadyFDA

James CollinsDow Chemical

Michael FischmanIntel

Charles GeraciNIOSH/EID

Barbara Gibson3M

Harold HaaseLockheed Martin

William HalperinUMDNJ

Deanna HarkinsU.S. Army CHPPM

John HowardNIOSH/OD

Matt HullLuna Innovations

Jackie IsaacsNEU, Nano (NSEC)

Amy JonesLockheed Martin

Steve JoslinLuna Innovations

Anthony KlapperReed Smith

Michael KosnettAm Coll Med ox

Eileen KuempelNIOSH/EID

abitha MaherAltairnano

Robert McCunneyMI

(Continued)


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James MeliusLIUNA

George MellendickPfizer

Michael MuhmBoeing

Diane Mundt

Environ International Corp

Kenneth Mundt

Environ International Corp

Vladimir Murashov

NIOSH/OD

Michael NasterlackBASF

Minda NieblasOSHA

Lyn PennimanOSHA

John PiacentinoNIOSH/OD

Scott ProtheroEPA

Anita SchillNIOSH/OD

Mary Schubauer-BeriganNIOSH/DSHEFS

Paul SchulteNIOSH/EID

John SestitoNIOSH/DSHEFS

Clifford StraderDOE

Pat SullivanNIOSH/DRDS

Marie SweeneyNIOSH/DSHEFS

Douglas routNIOSH/DSHEFS

David WarheitDuPont

Norbert WillClariant

Ralph ZumwaldeNIOSH/EID

Attendees and Participants: Workshop on occupational health surveillance

and nanotechnology workers. April 1718, 2007, Arlington, VA.(Continued)


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1

Interim Guidance for the Medical Screening andHazard Surveillance for Workers Potentially

Exposed to Engineered Nanoparticles

Introduction

Nanotechnology is a system o innovativemethods or controlling and manipulatingmatter at the near-atomic scale to produceengineered materials, structures, and devices.Engineered nanoparticles are generally con-sidered to include a class or subset o thesemanuactured materials with at least one di-mension o approximately 1 to 100 nanome-ters (www.nano.gov/html/acts/whatIsNano.html). At these scales, materials ofen exhibitunique properties beyond those expected at thechemical or bulk level that affect their physical,

chemical, and biological behavior. Te termultrafine is also requently used in the litera-ture to describe particles with dimensions lessthan 100 nanometers that have not been inten-tionally produced (e.g., manuactured) but arethe incidental products o processes involv-ing combustion, welding, or diesel engines. Itis currently unclear whether a distinction inparticle terminology is justified rom a saetyand health perspective i the particles have the

same physicochemical characteristics.Te potential occupational health risks associ-ated with the manuacture and use o nanoma-terials are not yet clearly understood. Many en-gineered nanomaterials and devices are ormedrom nanometer-scale particles (i.e., nanopar-ticles) that are initially produced as aerosols orcolloidal suspensions. Exposure to these mate-

rials during manuacturing and use may occurthrough inhalation, dermal contact, or inges-tion; however, inhalation exposure is the main

route o concern [ASCC 2006]. Tere is verylimited inormation available about dominantexposure routes, the potential or exposure,and material toxicity.

At this time, society in general and companiesin particular are aced with the dilemma o bal-ancing a desire to expand a potentially boun-tiul technology against the potential hazardsthat may result. Te real risks rom the technol-ogy are not known, and the perceived risks are

undetermined. In this regard, nanotechnologyis no different rom any other emerging tech-nology. One o the first areas where exposuresto engineered nanoparticles will occur is in theworkplace. In the ace o uncertainty about thehazards o nanoparticles, a corporate or soci-etal response (such as implementing appropri-ate occupational health surveillance measures)may assure the public that appropriate effortsare being taken to identiy and control poten-tial hazards in a timely ashion.

Concerned individuals rom government, in-dustry, labor, and academia, together with oc-cupational health proessionals and medicalpersonnel, have raised questions about whetherworkers exposed to engineered nanoparticlesshould be provided some type o medical sur-veillance. Te purpose o this document is to


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2 NIOSH CIB 60 Medical Screening of Workers

provide interim guidance concerning specificmedical screening or these workersthat is,medical tests or asymptomatic workersuntil

additional research either supports or negatesthe need or this type o screening. Te typeand degree o screening recommended here isin addition to any medical surveillance takingplace as part o existing occupational healthsurveillance efforts.

Background: A Brief Review of

the Literature

Effects of Exposure to Ultrafine

Particles

Results rom epidemiological studies in thegeneral population have shown associations be-tween fine particulate air pollution and increasedmorbidity and mortality rom respiratory andcardiopulmonary disease [Dockery et al. 1993;Ibald-Mulli et al. 2002; Pope et al. 2004]. Otherstudies have investigated specific markers o e-

ect associated with exposure to the ultrafineparticulate raction o air pollution [Ruckerl etal. 2006]. Studies o workers exposed to ultrafineparticles (e.g., diesel exhaust and welding ume)have reported elevated lung cancer risks [Steen-land et al. 1998; Garshick et al. 2004; Antonini2003] while results rom some animal studieshave shown that many types o poorly solubleultrafine particles can elicit a greater pulmonaryinflammatory response than larger particles othe same composition on a mass or mass basis

[Oberdrster et al. 1994; Lison et al 1997; Zhanget al. 2000, 2003; Brown et al. 2001; Hhr et al.2002; Duffin et al. 2007]. oxicological studiesindicate that the chemical and physical proper-ties that influence the toxicity o ultrafine parti-cles may also be relevant to mechanisms that in-fluence the toxicological response to engineerednanoparticles [Castranova et al. 2000; Aitken et

al. 2004; Donaldson et al. 2005, 2006; Maynard

and Kuempel 2005; Oberdrster et al. 2005a,b; Kreyling et al. 2006; Gwinn and Vallyathan

2006; Borm et al. 2006; Helland et al. 2007].Studies have also shown that physicochemicalproperties such as surace reactivity, chemicalcomposition, crystal structure, and shape also

influence the toxicity o nanoscale particles[Zhang et al. 1998; Dick et al. 2003; Warheitet al. 2007a, b]. Adverse effects reported rom

exposure to ultrafine particles have raised con-cerns about workers exposed to engineerednanoparticles [Royal Society and Academy

o Engineering 2004; Maynard and Kuempel2005; IRRS 2006; Nel et al. 2006; Schulte andSalmanca-Buentello 2007; Maynard 2007; Lam

et al. 2006; Kuempel et al. 2007; Aitken et al.2004; ASCC 2006]

Effects of Exposure to Engineered

Nanoparticles

Animal studies with some types o engineered

nanoparticles have caused adverse lung effects(e.g., pulmonary inflammation and progressivefibrosis) [Lam et al. 2004, 2006; Shvedova etal. 2005; akagi et al. 2008; Poland et al. 2008]

and cardiovascular effects (e.g., inflammation,blood platelet activation, plaque ormation,and thrombosis) [Radomski et al. 2005; Don-

aldson et al. 2006; Li et al. 2007]. Other studieshave demonstrated that discrete nanoparticlesmay enter the bloodstream rom the lungs andtranslocate to other organs [Oberdrster et

al. 2002] while other studies have shown thatdiscrete nanoparticles (35-37 nm count me-dian diameter) that deposit in the nasal region

may be able to enter the brain by translocationalong the olactory nerve [Oberdrster et al.2005(b); Elder et al. 2006]. A broader review

o the human and animal data can be oundin the NIOSH document Approaches to Safe


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3NIOSH CIB 60 Medical Screening of Workers

Nanotechnology: An Information Exchange withNIOSH [NIOSH 2006a].

Occupational Health

Surveillance

NIOSH has historically recommended imple-menting occupational health surveillance pro-grams when workers are exposed to potentiallyhazardous materials. Occupational health sur-veillance involves the ongoing systematic col-lection, analysis, and dissemination o expo-sure and health data on groups o workers or

the purpose o preventing illness and injury.Tis inormation is requently used or estab-lishing and evaluating the hierarchy o pre-ventive actions [Halperin 1996]. Te generalterm occupational health surveillance includesmedical and hazard surveillance. Occupationalhealth surveillance is an essential componento an effective occupational saety and healthprogram [Harber et al. 2003; NIOSH 2006b;Wagner and Fine 2008; Baker and Matte 2005].

While this document supports that concept, themain focus is whether a typical medical surveil-lance program that includes additional medicalscreening is warranted for workers potentiallyexposed to engineered nanoparticles.

Medical Surveillance

Medical surveillance targets actual healthevents or a change in a biologic unction o anexposed person or persons. Medical surveil-

lance is a second line o deense behind theimplementation o engineering, administra-tive, and work practice controls including theuse o personal protective equipment. NIOSHrecommends the medical surveillance o work-ers when they are exposed to hazardous ma-terials. Te elements o a medical surveillanceprogram generally include the ollowing:

An initial medical examination and collec-1.

tion o medical and occupational histories.

Periodic medical examinations at regularly2. scheduled intervals, including specific med-

ical screening tests when warranted.

More requent and detailed medical exami-3.

nations as indicated on the basis o findings

rom these examinations.

Post-incident examinations and medical4.

screening ollowing uncontrolled or non-routine increases in exposures such as spills.

Worker training to recognize symptoms o5.

exposure to a given hazard.

A written report o medical findings.6.

Employer actions in response to identifica-7.

tion o potential hazards.

When the purpose o a medical surveillance

program is to detect early signs o work-relat-

ed illness and disease, it is considered a type

o medical screening, also reerred to as medi-

cal monitoring and includes medical testing to

detect preclinical changes in organ unction or

changes beore a person would normally seek

medical care and when intervention is benefi-cial [Ashord et al. 1990; Baker and Matte 2005;

Halperin et al. 1986; Harber et al. 2003; ILO

1998]. Te establishment o a medical screen-

ing program should ollow established criteria

[Halperin et al. 1986; Borak et al. 2006; Baker

and Matte 2005; Harber 2003] and that specific

disease endpoints must be able to be deter-

mined by the test selected (see Appendix A).

Frequent Uses for Medical

Surveillance

Medical examinations and tests are used in

many workplaces to determine whether an

employee is able to perorm the essential


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unctions o the job, with or without reason-able accommodation, without posing a directand imminent threat to the saety or health o

the worker or others. Workplace medical ex-aminations must be conducted in compliancewith the Americans with Disabilities Act o1990 (ADA) (Public Law No. 101-336). Forexample, this law prohibits making a job offercontingent upon the applicants submission toa medical examination. Still, medical examina-tions and examinations conducted beore plac-ing a worker in a given job could potentiallyprovide useul baseline inormation in a vari-

ety o ways. For example, even i there appearsto be no reason or immediate concern aboutexposure to engineered nanoparticles in a par-ticular workplace setting, this type o baselinedata may benefit employers and workers alikei questions come up later regarding potentialworker health problems associated with thespecific engineered nanoparticle.

Medical surveillance o workers is also re-quired by law when there is exposure to a spe-

cific workplace hazard. Although OSHA doesnot have a standard that specifically addressesoccupational exposure to engineered nano-particles, OSHA has a number o standardsthat require medical surveillance o workers.Workplaces with engineered nanoparticlescomprised o chemicals addressed by currentOSHA standards (Appendix B) are subject tothe requirements o those standards, includingthe requirements or medical surveillance. Inaddition, medical surveillance o workers han-dling engineered nanoparticles may also betriggered when workers are exposed to otherhazardous substances (e.g., those listed in Ap-pendix B) present in nanoparticle operations.

In addition to substance-specific standards,OSHA has standards with broader applicabil-ity. For example, employers must ollow the

medical evaluation requirements o OSHAs

respiratory protection standard [29 CFR

1910.134] when respirators are necessary to

protect worker health. Tis standard includeselements o medical surveillance. Likewise, the

OSHA standard or occupational exposure to

hazardous chemicals in laboratories [29 CFR1910.1450] requires medical consultation ol-

lowing the accidental release o hazardous

chemicals.

NIOSH also recommends medical surveillance

(including screening) o workers when there is

exposure to certain occupational hazards (Ap-pendix C). None o the hazards noted in Ap-

pendix C are identified as engineered nanopar-

ticles, but medical surveillance would apply to

workers exposed to nanoparticles comprisedo chemicals or which NIOSH has a recom-

mendation. Te medical surveillance o these

workers may provide useul inormation i

questions arise in the uture about the healtheffects o their exposure to nanoparticles.

Hazard Surveillance and Risk

Management

Hazard surveillance involves identiying poten-

tially hazardous practices or exposures in theworkplace and assessing the extent to which

they can be linked to workers, the effective-

ness o controls, and the reliability o exposuremeasures [Sundin and Frazier 1989; Froines et

al. 1989]. Hazard surveillance for engineered

nanoparticles is an essential component ofany occupational health surveillance effort

and is used for defining the elements of the

risk management program.One component

o a risk management program involves taking ac-

tion to minimize exposure to potential hazards. Inthe case o engineered nanoparticles, even in

the absence o adequate health inormation, an


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toxicity o engineered nanoparticles comparedwith the toxicity o larger particles o the samecomposition. Results rom a limited number o

experimental animal studies with engineerednanoparticles indicate the potential or respira-tory and circulatory effects [Aitken et al. 2004;Borm et al. 2006; ASCC 2006; IRRS 2006];however, it is not clear which effects are mostcritical, whether they are dose-dependent, andwhether these effects are relevant to humanexposure. Additional studies are needed todetermine the biological significance o differ-ent physicochemical parameters and whether

these parameters can be used to predict thepotential toxicity o other untested engineerednanoparticles.

When occupational health surveillance is beingestablished, it is necessary to understand therelative, absolute, and population-attributablerisks to workers who are handling engineerednanomaterials. Tis includes understandingthe hazard as well as the extent o exposureand ultimately the risk. Limited inormation

is available on these topics, but exposures maybe generally low relative to the airborne expo-sures o the same material in larger but respi-rable particle sizes. Te level o risk resultingrom lower exposures to nanomaterials is un-known. Ultimately, epidemiological studies oexposed workers will be needed to help assessexposure-response relationships. Althoughsuch studies are difficult to conduct, they aremore likely than medical screening to clariythe relationship between exposure and adverseeffects at this time.

Finally, there is not yet enough research tomake categorical determinations o the hazardsbased on combinations o physicochemical ac-tors [ASCC 2006; Aitken et al. 2004]. Althoughpreliminary studies indicate that while specificmedical screening may be warranted in the u-

ture, insufficient inormation is now availableto make any recommendations beyond hazard

surveillance. NIOSH will continue to assess the

scientific evidence and periodically update theguidance on medical screening.

Recommendations

Continued in vivoand in vitrotoxicological re-search is needed to identiy potential health end-points related to occupational exposure to engi-neered nanoparticles. Epidemiological studieso exposed workers will be needed to establish

associations between exposures to engineerednanoparticles and adverse health effects and to

assess other potential exposure-response rela-tionships. Research is needed to assess variouscandidate biological markers that may ultimate-ly be used in medical screening, including mo-lecular markers [Schulte 2005]. Tis research isneeded to assess sensitivity, specificity, and pre-dictive value o biomarkers and clinical tests thatmight be developed and used to screen workers

health. Determining sufficient positive predic-tive value o a screening modality to detect ad-verse health effects early enough in the courseo the disease to enable secondary prevention, isan important actor when considering medicalscreening efforts.

Te ollowing recommendations are providedor workplaces where workers may be exposedto engineered nanoparticles during the courseo their work.

Take prudent measures to

control exposures to engineered

nanoparticles.

A prudent approach to controlling exposuresto engineered nanoparticles has been describedin the NIOSH draf document Approaches to


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Safe Nanotechnology: An Information Exchangewith NIOSH[NIOSH 2006a].

Conduct hazard surveillance as the

basis for implementing controls.

o establish prudent measures or controllingexposure to engineered nanoparticles, it isimportant to identiy which jobs or processesinvolve the production or use o engineerednanoparticles. Employers should identiy anddocument the presence o engineered nano-particles in their workplaces and the work tasks

associated with them. Tis inormation willserve as the basis or applying various controlmeasures [NIOSH 2006a]. Hazard surveillanceprograms should be designed to address someor all o the ollowing questions:

What exposure agents are ound in theworkplace?

Are standardized, reliable, andpractical methods available ormeasuring workers exposures to theagents?

What exposure metrics (e.g., mass,particle count, particle suracearea) are most relevant to the mostimportant health concerns?

o what extent can specific exposures(e.g., nanoparticles) be linked topeople?

What actions have been taken

to control potentially hazardousexposures?

How effective are the controls (e.g.,engineering)?

Which agents affect the most workers?

What jobs or industries are most likelyto cause exposures to workers?

What health effects are most likelyrelated to these exposures?

How are specific occupational exposures changing over time?

Continue use of established medical

surveillance approaches.

Currently, there are many established uses ormedical surveillance by employers and occu-pational health practitioners (see Section 3.3).Tese may pertain to workers exposed to en-gineered nanoparticles, but they are not spe-

cifically ocused on them. Employers shouldcontinue using these established approaches tocollect data that may be inormative in the u-ture about whether there is an increase in therequency o adverse health effects related toexposure to engineered nanoparticles. NIOSHcontinues to recommend occupational healthsurveillance as an important part o an effec-tive risk management program. Lack o evi-dence or recommending medical screeningor workers potentially exposed to engineered

nanoparticles should not stop employers whowant to take additional precautions, includingmedical screening, beyond those already es-tablished. However, it is important to note thatnonspecific medical testing can have negativeconsequences such as adverse effects resultingrom tests (e.g., radiation rom chest radio-graphs), creating unnecessary anxiety in work-ers and employers rom alse-positive screen-ing tests, and the economic ramifications o

additional diagnostic evaluations [Nasterlacket al. 2007; Schulte 2005; Marcus et al. 2006].

NIOSH will continue to evaluate the useulnesso establishing exposure registries in work-places were there is potential exposure to engi-neered nanoparticles. As the understanding ooccupational exposure to engineered nanopar-ticles increases, the development o exposure


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registries may be needed to orm the basis oruture epidemiologic research (Appendix F).

Such registries probably need to cover work-

ers rom numerous companies to reflect thediversity o exposures, to account or the smallnumber o workers exposed at a given site, andto assess chronic health effects.

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APPENDIX A Critical Aspects of anOccupational Medical Screening Program

Assessment o workplace hazards

Identification o target organ toxicities or each hazard

Selection o test or each screenable health effect

Development o action criteria

Standardization o data collectionprocess

Perormance o testing

Interpretation o test results

est confirmation

Determination o work status

Notification

Diagnostic evaluation

Evaluation and control o exposure

Recordkeeping

[Baker and Matte 2005].


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APPENDIX B OSHA Standards That IncludeRequirements for Medical Surveillance

2-acetylaminofluorene ethylene oxide

acrylonitrile ethyleneimine

4-aminodiphenyl ormaldehyde

inorganic arsenic hazardous waste

asbestos lead

benzene methyl chloromethyl ether

benzidine alpha-naphthylamine

bis-chloromethyl ether beta-naphthylamine

1,3butadiene methylene chloride

coke oven emissions 4-nitrobiphenyl

cotton dust n-nitrosodimethylamine

dibromochloropropane beta-propriolactone

3.3-dichlorobenzidine vinyl chloride

4-dimethylaminoazobenzene methylenedianiline

cadmium bloodborne pathogens

occupational exposure to hazardous chemicals in thelaboratories

chromium (VI)


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APPENDIX C Hazards for Which NIOSH HasRecommended the Use of Medical Surveillance

NIOSH publication number Title and date NTIS stock number

76195 Acetylene (1976) PB 267068

77112 Acrylamide (1976) PB 273871

78116 Acrylonitrile (1978) PB 81225617

77151 Alkanes (C5-C8) (1977) PB 27381776204 Allyl Chloride (1976) PB 267071

74136 Ammonia (1974) PB 246699

78216 Antimony (1978) PB 81226060

74110 Arsenic, Inorganic (1974),(Revised 1975)

PB 228151

75149 Arsenic, Inorganic (1975) PB 246701

7210267 Asbestos (1972) PB 209510

77169 Asbestos (Revised) (1976) PB 273965

78106 Asphalt Fumes (1977) PB 277333

74137 Benzene (1974) PB 246700

* Benzene (Revised) (1976) PB 83196196

77166 Benzoyl Peroxide (1977) PB 273819

78182 Benzyl Chloride (1978) PB 81226698

7210268 Beryllium (1972) PB 210806

* Beryllium (Revised) (1977) PB 83182378

2-Butoxyethanol[See: Ethylene Glycol Monobutyl Ether]

77122 Boron rifluoride (1976) PB 274747

76192 Cadmium (1976) PB 274237

77107 Carbaryl (1976) PB 273801

78204 Carbon Black (1978) PB 81225625

76194 Carbon Dioxide (1976) PB 266597

(continued)


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77156 Carbon Disulfide (1977) PB 274199

7311000 Carbon Monoxide (1972) PB 212629

76133 Carbon etrachloride (1975) PB 250424

* Carbon etrachloride (Revised) (1979) PB 83196436

76170 Chlorine (1976) PB 266367

75114 Chloroorm (1974) PB 246695

* Chloroorm (Revised 1979) PB 83195856

77210 Chloroprene (1977) PB 274777

7311021 Chromic Acid (1973) [Revised; see Chromium VI] PB 222221

760129 Chromium VI (1975) PB 248595

78191 Coal Gasification Plants (1978) PB 8016487495106 Coal Mine Dust PB 96191713

78107 Coal ar Products (1977) PB 276917

82107 Cobalt (1981) PB 82182031

7311016 Coke Oven Emissions (1973) PB 216167

80106 Confined Spaces, Working inConstruction [See: Excavations] (1979)

PB 80183015

75118 Cotton Dust (1974) PB 246696

78133 Cresol (1978) PB 86121092

77108 Cyanide, Hydrogen and Cyanide Salts (1976) PB 266230

78115 Dibromochloropropane (1978)1,2-Dichloroethane [See: Ethylene Dichloride]

PB 81228728

96104 2-Diethylaminoethanol (1996) PB 96197371

78215 Diisocyanates (1978) PB 81226615

78131 Dinitro-ortho-Cresol (1978) PB 80175870

77226 Dioxane (1977) PB 274810

76128 Elevated Work Stations, Emergency Egress rom(1975)

PB 248594

76206 Epichlorohydrin (1976) PB 81227019

77221 Ethylene Dibromide (1977) PB 276621

76139 Ethylene Dichloride (1976) PB 85178275

78211 Ethylene Dichloride (1,2- Dichloroethane)(Revised) (1978)

PB 80176092

(continued)


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90118 Ethylene Glycol Monobutyl Ether and Ethylene

Glycol Monobutyl Ether Acetate (1991)

PB 91173369

91119 Ethylene Glycol Monomethyl Ether, EthyleneGlycol Monoethyl Ether, and Teir Acetates

PB 92167147

83103 Excavations, Development o Draf ConstructionSaety Standards or, Volume 1 (1983)

PB 84100569

* Excavations, Development o Draf ConstructionSaety Standards or, Volume 2 (1983)

PB 83233353

77152 Fibrous Glass (1977) PB 274195

76103 Fluorides, Inorganic (1975) PB 246692

77193 Fluorocarbon Polymers, Decomposition Productso (1977)

PB 274727

77126 Formaldehyde (1976) PB 273805

85116 Foundries (1985) PB 86213477

79133 Fururyl Alcohol (1979) PB 80176050

78166 Glycidyl Ethers (1978) PB 81229700

83126 Grain Elevators and Feed Mills (1983) PB 83138537

89106 Hand-Arm Vibration (1989) PB 90168048

83125 Guidelines or Controlling Hazardous EnergyDuring Maintenance and Servicing (1983)

PB 84199934

7210269 Hot Environments (1972) PB 210794

86113 Hot Environments (Revised 1986) PB 8621950878172 Hydrazines (1978) PB 81225690

Hydrogen Cyanide [See: Cyanide, Hydrogen andCyanide Salts]

76143 Hydrogen Fluoride (1976) PB 81226516

77158 Hydrogen Sulfide (1977) PB 274196

78155 Hydroquinone (1978) PB 81226508

75126 Identification System or OccupationallyHazardous Materials (1974)

PB 246698

76142 Isopropyl Alcohol (1976) PB 273873

* Kepone (1976) PB 8319617078173 Ketones (1978)

Labeling [See: Identification System orOccupationally Hazardous Materials]

PB 80176076

7311010 Lead, Inorganic (1972) PB 214265

78158 Lead, Inorganic (Revised) (1978) PB 81225278

Lockout/agout [See: Hazardous Energy]

(continued)


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76188 Logging rom Felling to First Haul (1976) PB 266411

76205 Malathion (1976) PB 267070

7311024 Mercury, Inorganic (1973) PB 222223

76148 Methyl Alcohol (1976)Methyl Chloroorm [See: 1,1,1-richloroethane]

PB 273806

77106 Methyl Parathion (1976) PB 274191

76138 Methylene Chloride (1976) PB 81227027

98102 Metalworking Fluids (1998) PB 99133910

77164 Nickel, Inorganic (1977) PB 274201

76141 Nitric Acid (1976) PB 81227217

78212 Nitriles (1978) PB 81225534

76149 Nitrogen, Oxides o (1976) PB 81226995

78167 Nitroglycerin and Ethylene Glycol Dinitrate (1978) PB 81225526

7311001 Noise (1972) PB 213463

2006123 Occupational Exposure to Reractory CeramicFibers

98126 Occupational Noise Exposure PB 98173735

83127 Oil and Gas Well Drilling (1983) PB 84242528

77115 Organotin Compounds (1976) PB 274766

84115 Paint and Allied Coating Products (1984) PB 85178978

76190 Parathion (1976) PB 274192Perchloroethylene [See: etrachloroethylene]

78174 Pesticides, Manuacture and Formulation PB 81227001

76196 Phenol (1976) PB 266495

76137 Phosgene (1976) PB 267514

77225 Polychlorinated Biphenyls (1977) PB 276849

84103 Precast Concrete Products Industry (1984) PB 85220051

88101 Radon Progeny in Underground Mines (1988) PB 88173455

77192 Refined Petroleum Solvents (1977) PB 85178267

2006123 Reractory Ceramic Fibers (2006) PB 20061123003

75120 Silica, Crystalline (1974) PB 246697

76105 Sodium Hydroxide (1975) PB 246694

83119 Styrene (1983) PB 84148295

74111 Sulur Dioxide (1974) PB 228152

* Sulur Dioxide (Revised) (1977) PB 83182485

74128 Suluric Acid (1974) PB 233098

(continued)


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77121 1,1,2,2-etrachloroethane (1976) PB 273802

76185 etrachloroethylene (Perchloroethylene) (1976) PB 266583

78213 Tiols: N-Alkane Mono, Cyclohexane, andBenzene (1978)

PB 81225609

78179 o-olidine (1978) PB 81227084

7311023 oluene (1973) PB 222219

7311022 oluene Diisocyanate (1973) [Revised; See:Diisocyanates]

PB 222220

76184 1,1,1-richloroethane (Methyl Chloroorm) (1976) PB 267069

7311025 richloroethylene (1973) PB 222222

77127 ungsten and Cemented ungsten Carbide (1977) PB 275594

7311009 Ultraviolet Radiation (1972) PB 214268

77222 Vanadium (1977) PB 81225658

78205 Vinyl Acetate (1978) PB 80176993

* Vinyl Chloride (1974) PB 246691

* Vinyl Halides (1979) PB 84125699

77140 Waste Anesthetic Gases and Vapors (1977) PB 274238

88110 Welding, Brazing, and Termal Cutting (1988) PB 88231774

75168 Xylene (1975) PB 246702

76104 Zinc Oxide (1975) PB 246693

*Denotes the absence o a publication number or that recommendations were provided in testimony by NIOSH tothe U.S. Department o Labor.

NIS [National echnical Inormation Service] Web site: http://www.ntis.gov


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APPENDIX D Discussion of OccupationalHealth Surveillance Programs with Medical

Screening

Occupational health surveillance programs ex-ist that may be useul as models on which tobase uture efforts in the management o occu-

pational exposures to one or more engineerednanoparticles together with any potential healthrisk(s) related to those exposures.

Occupational exposures to metalworking fluids(MWF) have been implicated in health prob-lems including a variety o dermatologic andrespiratory health conditions. In the NIOSHCriteria for a Recommended Standard: Oc-cupational Exposure to Metal Working Fluids[NIOSH 1998], medical monitoring (screening)

is recommended by NIOSH as part o a com-plete MWF saety and health program. Similarly,in the Saety and Health Best Practices Manualor Metalworking Fluids [OSHA, 2008], OSHArecommends a model or a medical monitoring(screening) program and provides inormationon implementation. Tese recommended pro-grams provide examples o how appropriate

occupational health surveillance principles

may be applied toward prevention and con-

trol o occupational exposures and associated

health risks. Although there are still scientificuncertainties related to occupational exposures

to MWF that require urther research, the rec-

ommendations or these medical monitoring

programs are based on evaluation o extensive

data concerning exposures, health effects, and

exposure-health effect relationships. As noted

in the NIOSH Criteria Document for a Rec-

ommended Standard, these recommendations

concerning MWF are made with the expecta-

tion that they will prevent or greatly reduce the

risk o adverse health effects in exposed work-

ers. Gathering exposure and health effect data

related to occupational exposure to engineered

nanoparticles will be essential when ormulat-

ing medical screening programs or workers

exposed to engineered nanoparticles.


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APPENDIX E Examples of Limitations in theEvidence Base for Specific Medical Screening of

Workers Exposed to Engineered Nanoparticles

Key among the criteria or recommending spe-cific medical screening o workers exposed toengineered nanoparticles include determining

whether the substance in question is a hazardand whether the disease to be averted is su-ficiently common in the worker population tojustiy routine screening [Nasterlack et al. 2007;Borak et al. 2006; Halperin et al. 1986]. Forengineered nanoparticles, there is insufficientevidence or a definitive hazard determination.Only a small number o the myriad types oengineered nanoparticles have undergone ex-perimental animal inhalation testing, and nobroad categories o physicochemical risk ac-tors have been identified to allow or project-ing hazards across particle types. No chronicinhalation studies o engineered nanoparticleshave been conducted to date. Te existence oa ew short-term inhalation studies on carbonnanotubes and nanoscale metal oxides is notadequate to identiy what disease endpoints toassess in medical screening. Tere is also insu-ficient inormation available regarding the ab-solute, relative or population-attributable risks

associated with nanoparticle exposures [Nas-terlack et al. 2007].

Examples o the issues in determining the ra-tionale or recommending medical screeningor workers potentially exposed to engineerednanoparticles are described as ollows.

Single-Walled Carbon

Nanotubes (SWCNTs)

Intratracheal (I) exposure to SWCNs hasbeen associated with interstitial fibrosis in the

rat (Lam et al. 2004]. Aspiration o purified SW-

CNs caused rapid and progressive interstitial

fibrosis in mice [Shvedova et al. 2005]. NIOSH

has also shown that inhalation o SWCNs

cause interstitial fibrosis [Shvedova et al. 2008].

Te problem is that purified SWCNs are not

redox reactive and the interstitial fibrosis is not

driven by oxidant generation and inflamma-

tion. Tereore, measurement o markers o oxi-dant stress or inflammation in humans would

not be predictive. I interstitial lung disease was

considered the health endpoint o concern,

monitoring o the carbon monoxide diffusion

capacity o the lung could be perormed nonin-

vasively. A significant decline in diffusion would

indicate a loss o alveolar-capillary gas exchange

and suggest early signs o pre-clinical disease.

Unortunately, virtually no published data ex-

ist on occupational exposure concentrations orworking in SWCN operations. Consequently,

there is too little inormation available at this

time to veriy disease endpoints. Tere is also

too little inormation available on exposure in

general and ultimately the risk to workers who

handle these materials.


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Nanoscale Metal Oxides

Pulmonary exposure to nanoscale metal ox-

ides such as titanium dioxide (iO2) have beenshown in rat models to cause pulmonary in-flammation [Oberdrster et al. 2005] and toinhibit the ability o the systemic microvas-culature to respond to dilators [Nurkiewiczet al.2006; Nurkiewicz et al. in press] aferI or inhalation exposures. Ultrafine (nano-scale) iO

2has been shown to be more potent

in causing these effects than fine iO2 on an

equivalent mass basis. Tese effects have been

associated with oxidant stress and induction oinflammatory mediators. Tereore, markerso oxidant stress and inflammation could beconsidered as early indicators o human expo-sure or response. Oxidant stress markers havebeen suggested as markers o toxicity to metaloxide nanoparticles as a class [Nel et al. 2006].Examples o such markers would be nitrousoxide or isoprostanes in exhaled breath orblood markers o oxidant stress. However, theutility o these markers or screening workers

exposed to engineered nanoparticles has notbeen demonstrated. In addition, some researchshows that nanoscale iO

2 is linked to cancer

o the lung and the International Agency orResearch on Cancer (IARC) has categorized ti-

tanium dioxide as a possible carcinogen to hu-

mans [IARC 2006]. Nonetheless, no evidence

clearly demonstrates that medical screening

o asymptomatic workers exposed to lung car-

cinogens decreases the chance o dying rom

cancer (NCI 2007; Marcus et al. 2006).

Nanoscale Cadmium

Cadmium is a substance that has medical screen-

ing recommendations or workers exposed in or-

der to prevent or assess lung and kidney toxicity

(see Appendices B and C). At a minimum, these

recommendations should pertain to nanoscalecadmium (e.g., such as that used in the produc-

tion o quantum dots). Medical screening is

typically triggered by the airborne concentra-

tion o the substance in the workplace (e.g., the

action level concentration). An action level is

some raction, usually 50%, o an occupational

exposure limit (OEL). Whether the action level

concentration recommended or nonnanoscale

cadmium particles is adequate or nanoscale

cadmium is unknown. Workplaces with en-gineered nanoparticles o materials addressed

by current OSHA standards are subject to the

requirements o those standards, including the

requirements or medical surveillance.


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APPENDIX F Exposure Registries

Exposure registries are useul tools or surveil-lance o new or perceived hazards. A registryprovides a structured and orderly approach tohandling the problem o identiying and main-taining communication with workers exposed tohazardous substances [Schulte and Kaye 1988].An exposure registry is the enrollment o persons

exposed or likely to have been exposed to occupa-tional or environmental hazards; the registry mayinclude how these groups are managed with re-gard to primary or secondary preventive efforts.In occupational situations, company employeerosters are de acto registries; however, they maynot address employees who leave a company.Moreover, or a new cross-cutting technologysuch as nanotechnology, the registry could enrollpersons rom various companies. Generally, ex-posure registries are developed and maintained

by government entities, but there are exampleso private-sector registries related to exposure tocommercial products.

Te purposes and unctions o exposure regis-tries may be summarized as ollows:

Delineate a population at risk

Follow cohort to ascertain exposure-dis-ease associations

Follow cohort to ensure the institution o

appropriate primary and secondary pre-vention and medical surveillance

Follow cohort to allow or appropriate so-cial, legal, and economic support

Demonstrate societal concern or the co-hort and provide a base or political ac-tion relevant to the exposure

Notiy a cohort o an exposure, preven-tive measures, or therapeutic advancesthat were not understood or known at thetime the registry was established

Various issues should be addressed when con-sidering development o exposure registries.Tese include the term o the registry, needs o

registrants, confidentially o inormation, cost omaintaining the registry, and the potential impacto the registry on workers and companies.

Registries are essentially a collection o individ-ual worker inormation over time with at leasta preliminary plan or analysis. Data collectedin registries may be subject to limitations. Ex-posure registries are not always useul in eti-ologic research. For diseases with low preva-lence ollowing low-level exposures, exposureregistries are not very effective tools because(1) exposure classification is ofen difficult,(2) the statistical power o prospective studiesis low, and (3) the time period o the study maybe impractically long. Moreover, changes inexposures experienced by registry participantsover time may complicate the ability to estab-lish clear exposure-disease relationships.

Exposure registries may provide opportunities

to determine the exposure-disease associationand risk. Also, when practical prospective stud-ies can be designed, registries can be used to es-tablish hypotheses. Many questions arise whenconsidering an exposure registry or etiologicresearch, including:

How can exposed persons be adequatelydifferentiated rom nonexposed persons?


36/40


What group could serve as a comparison

group so that the disease experience o the

exposed group can be evaluated?

How long should the group be ollowed?

Although exposure registries are useul tools to

assist populations potentially at risk, their util-

ity or workers exposed to engineered nano-particles needs urther evaluation.


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Notes


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Notes


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Current Intelligence Bulletin 60

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