Lung Function 

(Spirometry) Testing 

in Employees 

at a Flavorings 

Manufacturing Plant --- 

Indiana

Health Hazard Evaluation Report

HETA 2008-0155-3131

June 2011

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

Workplace

Safety and Health

 National Institute for Occupational 

Safety and Health

This Health Hazard Evaluation (HHE) report and any recommendations made herein are for the specific 

facility evaluated and may not be universally applicable. Any recommendations made are not to be 

considered as final statements of NIOSH policy or of any agency or individual involved. Additional HHE 

reports are available at http://www.cdc.gov/niosh/hhe/

Kathleen Kreiss, MD 

Chris Piacitelli, CIH

Jean Cox-Ganser, PhD
The employer shall post a copy of this report for a 

period of 30 calendar days at or near the workplace(s) 

of affected employees. The employer shall take steps 

to insure that the posted determinations are not altered, 

defaced, or covered by other material during such 

period. [37 FR 23640, November 7, 1972, as amended 

at 45 FR 2653, January 14, 1980].
Health Hazard Evaluation Report 2008-0155-3131 Page i

Report Abbreviations................................................................................................ii

Highlights of the NIOSH Health Hazard Evaluation........................iii

Summary ........................................................................................................vi

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

Background ....................................................................................................1

Assessment.....................................................................................................2

Results........................................................................................................... 10

Discussion.................................................................................................... 25

Conclusions................................................................................................. 33

Recommendations.................................................................................... 33

References.................................................................................................... 37

Contents

Acknowledgments Acknowledgements and Availability of Report ............................. 40
Page ii Health Hazard Evaluation Report 2008-0155-3131

ACOEM American College of Occupational and Environmental Medicine

HHE Health hazard evaluation

FEMA Flavor and Extract Manufacturers Association

FEV1 Forced expiratory volume in one second

FVC Forced vital capacity

IH Industrial hygiene

LEV Local exhaust ventilation

LLD Limit of longitudinal decline

LLN Lower limit of normal

MDC Minimum detectable concentration

mL Milliliters

mL/year Milliliters per year

MSDS Material safety data sheet

NIOSH National Institute for Occupational Safety and Health

NTIS National Technical Information Service

OSH Occupational Safety and Health

OSHA Occupational Safety and Health Administration

ppm Parts per million

RDHETAP Respiratory Disease Hazard Evaluation and Technical Assistance Program 

Abbreviations
Health Hazard Evaluation Report 2008-0155-3131 Page iii

Introduction

The National Institute for Occupational Safety and Health 

(NIOSH) received a union request for a health hazard evaluation 

(HHE) at a flavorings manufacturing facility in Indiana. A local 

branch of the International Brotherhood of Teamsters submitted 

the HHE request because it was concerned about possible 

respiratory problems and the use of flavoring chemicals, including 

diacetyl, at the facility. NIOSH investigators conducted a site visit 

in May 2008 and received records of spirometry, a type of lung 

function test, in June 2008. After a delay incurred by litigation, 

the company provided additional spirometry records through 

September 2009, job history information for current employees, air 

sampling results through August 2009, and respiratory protection 

and hazard communications programs information. 

What NIOSH Did

● NIOSH investigators visited the facility on May 29-30, 2008.

● We performed limited air sampling for volatile organic 

compounds at the facility and reviewed company air 

sampling records.

● We analyzed employees’ spirometry reports in relation to 

work history information and assessed whether abnormalities 

in tests were related to work factors.

What NIOSH Found

● There were 34/106 employees (32%) with abnormal 

spirometry: 30/106 (28%) had a restrictive pattern of 

abnormality, 3/106 had an obstructive pattern and 1/106 

had a mixed obstructive and restrictive pattern.

● The prevalence of restriction in most recent spirometry 

reports was 3.8 times higher than expected in the U.S. 

population.

● For the 18 employees with spirometry tests performed for all 

four years from 2006 to 2009, there were parallel declines in 

mean percent predicted forced expiratory volume in 1 second 

(FEV1) and forced vital capacity (FVC) with relatively stable 

mean FEV1/FVC ratio, consistent with an evolving restrictive 

process during employment. 

● Depending on the values used to determine the threshold 

for abnormal decline in FEV1 over time, between 17%-19% 

Highlights of the

NIOSH Health

Hazard Evaluation
Page iv

Highlights of the

NIOSH Health

Hazard Evalution

(continued)

Health Hazard Evaluation Report 2008-0155-3131

of 70 employees with good quality longitudinal spirometry 

testing had abnormal declines. 

● Five of 13 employees with excessive decline still had normal 

values for FEV1, which means they would not be identified 

as abnormal if their repeat measurements over time were not 

compared to each other. 

● Employees who worked in liquid compounding, process 

flavors, dry blend, extract and distillation, and spray dry 

(areas we categorized as having higher potential for flavoring 

exposures) had 2.8 times greater average annual declines in 

FEV1 and were about 7 times more likely to have abnormal 

declines in FEV1 than employees in other areas. 

● The work-related declines in lung function in plant 

employees might be related to exposures other than diacetyl.

● Diacetyl has been measured in the air in many areas of the 

plant.

What Managers Can Do

● Explain to employees that there appears to be a lung hazard 

in this facility related to exposure to flavoring chemicals and 

train them to minimize exposure.

● Lower exposures to flavoring chemicals by engineering 

controls, work practice modifications, administrative 

measures, and respiratory protection until medical 

monitoring documents that employees are no longer at 

excess risk of developing occupational respiratory disease.

● Obtain baseline breathing tests (spirometry) before new 

employees are exposed to flavoring chemicals.

● Perform breathing tests every 3 months on all employees 

in areas with higher potential for exposure to flavoring 

chemicals and all employees with abnormal declines until 

abnormal declines in the work force have been controlled by 

lowering exposures.

● Perform breathing tests every 6 months on employees in 

areas with lower potential for flavoring exposures.

● Ask the occupational health clinic to refer all employees with 

abnormal restrictive patterns on spirometry to lung specialists 

for definitive tests to establish whether lung disease is the 

cause of restriction. All employees with abnormal obstructive 

patterns need referral for diagnosis, as well.
Page v

Highlights of the

NIOSH Health

Hazard Evalution

(continued)

Health Hazard Evaluation Report 2008-0155-3131

● Ask the occupational health clinic to notify employees of 

abnormal falls in breathing tests, even if the results remain 

within the normal ranges of FEV1 and FVC. Measures 

should be taken as listed above to protect these employees 

from potentially harmful exposures. They should have follow 

up spirometry testing at 3 month intervals at least until their 

lung function has stabilized.

● Ask the occupational health clinic to analyze the spirometry 

findings for the whole employee population to determine 

whether processes continue to be associated with 

increased risk of abnormalities so that enhanced medical 

monitoring, work limitation, and exposure reduction can be 

implemented and prioritized.

What Employees Can Do

● Minimize exposure to flavoring chemicals.

● Use your respirator at all times when handling flavoring 

chemicals or near co-workers handling flavoring chemicals.

● Participate in company-scheduled breathing tests 

(spirometry). Ask if your lung function is declining 

excessively and if you have abnormalities on spirometry.

● Seek further medical evaluation if your lung function 

is declining excessively or if you have abnormalities on 

spirometry.

● Take this report to your doctor if you develop persistent 

cough, trouble breathing, abnormal spirometry, or abnormal 

drop in spirometry measurements on your latest breathing 

test compared to previous tests.

● Call NIOSH at 1-800-232-2114 if you have any questions 

about this report or your spirometry results.
Page vi Health Hazard Evaluation Report 2008-0155-3131

In March 2008, an International Brotherhood of Teamsters 

local union requested a health hazard evaluation at a flavoring 

manufacturing company because of concern about possible lung 

effects of flavoring exposures, including diacetyl. In May 2008, 

NIOSH conducted a brief walk-through visit of the company. 

Subsequently, the company brought litigation to prevent further 

on-site evaluations. In June 2009, after resolution of the litigation, 

the company agreed to provide NIOSH with various medical and 

workplace information. All information was received by November 

2009. 

NIOSH staff evaluated spirometry data supplied by the company 

on production employees tested from 1998 through 2009. The 

majority of the spirometry tests was performed in the years 2004 

and later. We classified spirometry tests for quality and compared 

the prevalence of abnormalities in acceptable quality tests to 

national population prevalence, adjusted for the distributions of 

age, sex, race, smoking, and body mass index in the company’s 

employees. We calculated declines over time in forced expiratory 

volume in 1 second (FEV1), a lung function measurement made 

using spirometry, for employees with more than one spirometry 

test of acceptable quality, since excessive decline in FEV1 can be 

an early marker of lung disease. Using an approach that adjusts for 

quality of a spirometry monitoring program, reflected by withinperson variation, we compared the declines in lung function to a 

statistically-determined lower limit of normal decline. 

After establishing which employees had abnormal declines in lung 

function, we evaluated work area risk factors for associations with 

excessive declines in lung function, adjusted for age, smoking, 

tenure, change in weight, and obesity. Based on our experience in 

other flavoring plants, we designated a group of areas with higher 

potential for flavorings exposure as a possible risk factor. These 

were liquid compounding, process flavors, dry blend, extract and 

distillation, and spray dry. We compared spirometric findings for 

employees in these areas with employees who worked in other 

areas of the plant. We also evaluated environmental monitoring 

measurements supplied by the company before and after our walk 

through visit, along with the four measurements conducted during 

the walk through. 

The flavorings manufacturing company supplied spirometry data 

on 112 employees; 75% of these employees had more than one 

test session, with a follow-up range of 0.5 to 11 years. The most 

recent spirometry measurement for 106 employees with at least one 

spirometry test of acceptable quality showed that 30/106 (28%) 

 Production employees 

at this flavoring 

manufacturing company 

had striking excesses of 

abnormal restrictive lung 

function and abnormal 

declines in lung function 

during employment. 

Employees with higher 

potential for exposure to 

flavorings had greater 

average annual decline 

in lung function and a 

7-fold higher chance of 

abnormal lung function 

decline than employees 

in other areas with 

lower potential for 

exposure. Additional 

medical testing will be 

needed to determine 

the underlying cause(s) 

of these abnormalities 

in lung function 

(spirometry) testing. It is 

especially important to 

determine if those with 

restrictive spirometry 

have occupational lung 

disease. In the meantime, 

efforts should be 

continued to minimize 

exposure to diacetyl 

and other potentially 

causative inhaled agents. 

Those with high potential 

exposures should be 

offered ongoing medical 

surveillance that follows 

spirometry over time 

to assist in identifying 

problems that can be 

corrected.

Summary
Page vii

Summary (continued)

Health Hazard Evaluation Report 2008-0155-3131

employees had restrictive abnormalities, 3/106 had obstructive 

abnormalities, and 1/106 had both restrictive and obstructive 

abnormalities. The 28% of employees with restrictive abnormalities 

was 3.8 (95% confidence interval 2.6–5.4) times higher than would 

be expected in a U.S. population with the same demographic 

characteristics. Among the 30 employees with restrictive 

abnormalities, 27% had longitudinal testing demonstrating 

abnormal declines in FEV1 over time, indicating that progressive 

deterioration in lung function had occurred; 17% had no history 

of longitudinal testing, and thus no evaluation for excessive decline 

over time was possible. In addition to the 34/106 (32%) with 

abnormal restrictive or obstructive spirometry, 5 employees with 

normal most-recent spirometry values had longitudinal testing 

demonstrating abnormal declines in FEV1 over time, which, if 

continued, might result in spirometric abnormality. Thus a total of 

39/106 (37%) employees among those with company spirometry 

measurements had evidence of some abnormality, either in 

classification of most recent spirometry as showing restriction or 

obstruction; and/or longitudinal spirometry showing excessive 

decline over time, with most recent spirometry values still within 

the normal range. Forty-two employees did not have serial data of 

adequate quality to allow evaluation for abnormal declines. 

The company’s 2009 exposure measurements documented 

that diacetyl was present in at least one sample in all sampled 

production areas, the laboratory, and the warehouse. Two of 

the four NIOSH area measurements detected diacetyl in liquid 

compounding and packaging areas. These findings supported our 

designation of a group of areas with higher potential for flavorings 

exposures, although some areas that were classified as being in the 

lower potential for exposure group did have exposures of concern. 

Employees who ever worked in areas with higher potential for 

flavorings exposure (liquid compounding, process flavors, dry 

blend, extract and distillation, and spray dry) had 2.8 times greater 

average annual declines in FEV1 than employees in areas with 

lower potential for flavorings exposure. In particular, employees 

who had ever worked in liquid compounding had statistically 

higher average annual declines in FEV1, compared to the lower 

potential for exposure group. Employees who currently worked 

in higher potential for flavorings exposure areas were 7 times 

more likely to have abnormal declines in FEV1 than employees in 

other areas, which is consistent with work-related risk for adverse 

respiratory health outcomes.
Page viii

Summary (continued)

Health Hazard Evaluation Report 2008-0155-3131

Additional medical testing is needed to determine whether the 

abnormal spirometry findings found among workers are due to 

lung disease. In particular, medical testing is needed to determine 

the underlying cause of restrictive spirometry. Although obesity 

is a major cause of restrictive abnormalities in the United States, 

our comparisons with the U.S. population were adjusted for the 

proportions of employees who were overweight or obese, as were 

our analyses of work area risk factors. Thus, restrictive spirometry 

in this workforce cannot be explained by obesity. Since the excess 

of spirometric abnormalities is substantial and the distribution 

of excessive declines in lung function is associated with history 

of working in areas with higher potential for exposure, there is 

great cause for concern about occupational lung disease. It is 

possible that some exposure other than diacetyl may underlie 

these abnormalities, since the predominant pattern of restrictive 

abnormalities differs from the pattern of obstructive abnormalities 

seen among microwave popcorn employees. Also, the flavorings 

used in this plant are more diverse than are found in microwave 

popcorn production. However, some diacetyl-exposed individuals 

in microwave popcorn plants and other settings have had restrictive 

abnormalities without other apparent cause. Thus, the spectrum 

of abnormalities caused by diacetyl might include restrictive lung 

disease. This possibility remains to be fully explored. 

We recommend further lowering of flavoring exposures, without 

regard to anticipated exposure limits to diacetyl, since other 

chemicals may be associated with the adverse respiratory health 

outcomes documented in the workforce. We reiterate our interim 

report recommendations for engineering controls, work practices, 

enhanced respiratory protection, and medical surveillance. 

Ongoing medical surveillance that uses longitudinal spirometry 

testing to monitor those with potentially harmful exposures is also 

recommended, particularly until the cause of the high burden of 

abnormal spirometry in the workforce is fully understood. The 

company’s contract with its medical provider should provide for 

aggregate epidemiologic analysis of the medical results, including 

analysis of medical results by department or job. Aggregate analysis 

can identify hazards associated with flavoring manufacture and may 

assist the company in targeting priorities for prevention through 

exposure control.

Keywords: NAICS 311930 (Flavoring Syrup and Concentrate 

Manufacturing), Flavorings, Diacetyl, Butter, Respiratory 

Symptoms, Spirometry, Restriction. 
Health Hazard Evaluation Report 2008-0155-3131 Page 1

Introduction

NIOSH received an HHE request on March 19, 2008 from a local 

branch of the International Brotherhood of Teamsters to evaluate 

both the respiratory health and exposures of production employees 

who handle flavoring chemicals at a flavorings manufacturing 

facility in Indiana. While no health effects were reported, 

employees were concerned about exposure to flavorings including 

diacetyl, a butter flavoring constituent used in the facility. 

Background Increasing cumulative exposure of workers to diacetyl has been 

associated with an increased prevalence of abnormal lung 

function [Kreiss et al. 2002; Kullman et al. 2005; NIOSH 2004]. 

In animal experiments conducted by NIOSH, rats exposed to 

vapors from diacetyl developed severe injury to their airways 

[Hubbs et al. 2004]. After investigating several microwave 

popcorn plants and finding that employees with occupational 

exposures to flavorings were at risk for fixed obstructive airways 

diseases, NIOSH disseminated an ALERT to raise awareness of 

the inhalation risk posed by flavorings chemicals and to provide 

preventive recommendations [NIOSH 2004]. Because of sufficient 

evidence from epidemiologic studies and animal experiments 

that diacetyl causes airways obstruction and excessive decline in 

FEV1 [Kreiss 2007b], efforts to regulate diacetyl exposures are 

underway. However, the full spectrum of lung disease associated 

with flavoring exposures is still under investigation. In addition to 

obstructive lung disease, this spectrum may also include restrictive 

lung disease [Day et al. 2011, Akpinar-Elci et al. 2004, Kreiss 

2007a]. 

In May 2008, NIOSH conducted an initial site visit at the facility 

in Indiana and at their contracted occupational clinic. The facility 

produces a variety of flavor formulations in liquid, paste, and 

powder form. Some examples of flavorings produced include 

butter, buttermilk, cheese, sour cream, coffee, orange, blueberry, 

raspberry, grape, beef, chicken, and fish. At the time of the site 

visit, the facility employed about 115 production employees and 

about 100 office employees. The production is a batch process and 

takes place over three shifts, five days a week. Major production 

areas include extract and distillation, X-Oil, liquid compounding, 

process flavors, dry blend, spray dry, and packaging. Other work 

areas include shipping, warehouse, maintenance, quality control, 
Page 2 Health Hazard Evaluation Report 2008-0155-3131

On May 29 and 30, 2008, NIOSH conducted an initial site 

visit at the facility in Indiana. The NIOSH field team for the 

site visit consisted of two physicians, an industrial hygienist, 

and a mechanical engineer. We met with union representatives, 

production employees, management, and attorneys. We conducted 

limited sampling for volatile organic compounds. On the 

afternoon of May 30, 2008, we visited the contracted occupational 

health clinic that conducts the facility’s spirometry testing, medical 

clearance for respirator use, and respirator fit testing for its 

employees. While on site, we briefly reviewed available spirometry 

reports for 85 current employees and 4 former employees. On June 

18, 2008, we received copies of the spirometry test results for 84 

current and 4 former employees, allowing more detailed review. 

In September 2009, the flavorings company provided additional 

spirometry reports for 96 current employees. In addition, the 

company provided work history information requested by NIOSH 

Background (continued)

research and development, and administration. Arrangements 

were made with the occupational clinic to obtain the results of 

employees’ spirometry, a lung function test that measures the 

volume and flow rate of air that can be blown out of the lungs after 

a full inspiration. In June 2008, we received copies of spirometry 

reports on facility production employees from the clinic. 

Our request for an additional site visit to assess exposures, 

interview employees, and conduct medical tests on employees 

was the subject of litigation brought by the company in Federal 

District Court, which was concluded in May 2009. In June 2009, 

we issued an interim report recommending further medical and 

environmental evaluation. After discussions in follow up, the 

company agreed to provide additional medical and environmental 

information to NIOSH. The company provided a table of their 

action items in response to the interim report in August 2009, 

updated medical information in September and October 2009, 

and air sampling results in November 2009. 

This final report provides results of analyses of all the spirometry 

records sent to NIOSH, information from the May 2008 site 

visit, updated information from the company, descriptions of the 

company’s responses to the recommendations given in the interim 

report, and additional recommendations based on our subsequent 

findings.

Assessment
Health Hazard Evaluation Report 2008-0155-3131 Page 3

in order to evaluate the spirometry results in relation to job. In 

October 2009, we requested diagnostic medical test results from 

the contracted clinic for any employees that had been referred for 

medical follow-up assessments. Some employees had been seen by 

a contract clinic physician to discuss abnormal spirometry results, 

but we received no additional information about diagnostic testing 

done to determine the cause of abnormal spirometry results. In 

November 2009, the company provided updated air sampling 

results and information on their respiratory protection and hazard 

communication programs. 

Demographic information

We abstracted information from spirometry records on gender 

and race, as well as the age, height, and weight of each employee 

on their test date. The spirometry records usually provided 

information on smoking status at the time of the test (Y/N). We 

used this smoking status data to create a dichotomous smoking 

variable, which indicated whether or not a person was ever 

categorized as a smoker at any testing interval. 

Work history information

In September 2009, we received work history information for 97 

current and former employees. Work history information included 

job title and the start dates for each job title. The work history also 

indicated if a person had been terminated. We had spirometry 

records but no work history information for 15 employees. We had 

work history information but no spirometry record for 1 employee. 

We used the dates in the work history information to calculate 

total tenure in years. The job titles supplied by the company 

identified the area where the employee worked and the job he/

she performed in that area. There were 12 areas identified: 

administration, dry blend, extract and distillation, liquid 

compounding, maintenance, packaging, process flavors, sample 

ordering, spray dry, warehouse, quality control, and research and 

development. Because a relatively small number of people worked 

in the quality control and research and development areas and 

because it is likely that employees in these two areas experienced 

similar levels of exposure to flavoring chemicals, we combined 

the quality control and research and development areas into one 

category for our analyses. Based on information obtained from the 

site visit about where liquid and dry flavorings were produced and 

Assessment (continued)
Page 4 Health Hazard Evaluation Report 2008-0155-3131

Assessment (continued)

on work history information provided by the company, we assigned 

employees in the following areas to the category of higher potential 

for exposure to flavoring chemicals: dry blend, extract and 

distillation, liquid compounding, process flavors, and spray dry. 

We categorized the work history information four different ways: 

(1) currently working in an area; (2) ever worked in an area; (3) 

currently working in areas with higher vs. lower potential for 

exposure; (4) ever worked in areas with higher vs. lower potential 

for exposure. During the site visit in May 2008, the company 

provided a list of employees scheduled to work that day and a list 

of employees’ last spirometry results, which included information 

about which area the employees worked in. This information was 

used to supplement missing data for the 15 employees without 

work history information so they could be included in our ‘ever 

worked in an area’ analyses. 

Spirometry records evaluation

We evaluated 369 spirometry records measuring exhaled air 

volumes and flow rates achieved during a maximal forced 

expiration after a full inspiration from a total of 112 employees. 

The records dated from July 6, 1998 to August 25, 2009.

Information from the records was entered into a database using a 

double entry system for quality control. We used SAS® (version 9.2, 

SAS Institute Inc., Cary, North Carolina, United States) statistical 

software to analyze the data. 

Two-thirds of the spirometry tests were performed using an 

EasyOneTM spirometer (ndd Medical Technologies, Andover, 

Massachusetts). The test reports for most of these included a 

quality grade. When reports did not include a quality grade (as 

was the case for 29 tests performed using an EasyOne spirometer 

and for 119 tests performed with another type of spirometer), 

we graded spirometry using the EasyOne Spirometry EasyGuide 

criteria from the version 4.0 manual. Spirometry tests graded 

A and B had at least three acceptable expiratory efforts, and 

measurements for FEV1 and FVC matched within 200 milliliters 

(mL) or less. Spirometry tests graded C had at least two acceptable 

efforts, and measurements for FEV1 and FVC matched within 250 

mL or less. Spirometry tests graded D had only one acceptable 

effort, or the two best acceptable measurements did not meet the 

250 mL criterion for repeatability. Spirometry graded F had no 

acceptable efforts. There were four tests performed with a different 
Health Hazard Evaluation Report 2008-0155-3131 Page 5

Assessment (continued)

model spirometer that did not have enough information about 

each individual expiratory effort to allow for a quality grade to be 

assigned. 

To classify whether employees’ spirometry test results were normal 

or abnormal, we compared each employee’s most recent spirometry 

test results to reference values (based on age, height, gender, and 

race) using a reference equation developed from U.S. population 

data from the Third National Health and Nutrition Examination 

Survey [Hankinson et al. 1999].1 For some individuals with more 

than one spirometry report, substantial variation was noted 

in recorded heights. For these individuals, we used the most 

frequently recorded height value (mode) to interpret spirometry 

results. When there was no mode height value, we used the mean 

of the reported heights.

Spirometry results with A, B, or C quality grade were able to be 

interpreted as normal or abnormal. If a test had a D quality grade 

but documented normal ventilatory function, it was interpreted 

as normal. If a test of D quality was consistent with abnormal 

ventilatory function, it was considered uninterpretable, because it 

was not possible to say if this finding was real or an artifact of poor 

test quality. If a test had an F quality grade, the test was considered 

uninterpretable. We classified abnormalities in spirometry 

test results as obstructive, restrictive, or mixed obstructive 

and restrictive (described below). We further categorized such 

abnormalities as mild, moderate, moderately severe, severe, or very 

severe based on the most recent guidance on interpreting lung 

function tests [Pellegrino et al. 2005].

In an obstructive pattern of abnormal spirometry, air is exhaled 

from the lungs more slowly than normal, as can be found in 

asthma, bronchitis, emphysema, and bronchiolitis obliterans. 

It is defined by an FEV1 below the lower limit of normal (LLN) 

and a reduced ratio of FEV1 to the total volume of air blown 

out of the chest during the forced expiration (FEV1/FVC). The 

greater the obstruction, the more difficult it is to exhale the air 

from the lungs. Individuals with evidence of airways obstruction 

on spirometry testing can be given a bronchodilator medication, 

followed by repeat spirometry, to see if the obstruction is reversible, 

1 The National Health and Nutrition Examination Survey is a program of 

studies designed to assess the health and nutritional status of adults and children in the 

United States. The survey combines interviews and physical examinations. It is a major 

program of the National Center for Health Statistics, a part of the Centers for Disease 

Control and Prevention. Information can be found at: http://www.cdc.gov/nchs/nhanes.

htm
Page 6 Health Hazard Evaluation Report 2008-0155-3131

Assessment (continued)

as is characteristic of asthma. In contrast, the obstruction found 

in flavoring-exposed individuals with bronchiolitis obliterans is 

irreversible. 

In a restrictive pattern of abnormal spirometry, the total amount 

of air exhaled is smaller than normal. Thus, this abnormality is 

defined by an FVC below the LLN, with a normal FEV1/FVC 

ratio. This type of abnormal spirometry often reflects a decreased 

volume of air in the lungs at full inspiration. It can occur in people 

with stiff lungs, such as is found in pulmonary fibrosis (lung 

scarring); people with weak respiratory muscles; or people who are 

considerably overweight. The greater the restriction, the greater will 

be the possible physical limitation. 

A mixed obstructive/restrictive pattern of abnormal spirometry is 

defined by an FVC below the LLN, with an FEV1/FVC ratio that is 

also below the LLN. A mixed pattern of abnormal spirometry can 

be seen in people who have severe airways disease in the absence 

of lung scarring, respiratory muscle weakness, or obesity; and in 

people with more than one type of disease process affecting the 

lungs.

We compared the prevalence of an abnormal restrictive pattern of 

spirometry with the prevalence that would be expected in the U.S. 

general population with the same distributions of age (less than 40 

years and 40 or older), sex, race, ethnicity, ever smoking (yes, no) 

and body mass index (less than 25, 25 to less than 30, and 30 or 

greater kilograms/meters2), which is a classification of overweight 

and obesity. The U.S. population prevalences were based on the 

third National Health and Nutrition Examination Survey [National 

Center for Health Statistics 1996].

Changes in lung function over time

In adulthood, it is normal for lung function to decline slowly as a 

person ages. After achieving highest levels of FEV1, sometimes as 

late as in their thirties, individuals lose about 20-30 mL/year on 

average [Sherrill et al. 1992]. An excessive rate of FEV1 decline can 

indicate developing lung disease. The ability to reliably detect small 

increases in rate of FEV1 decline, especially over time intervals of 

less than about 7 years, is influenced by the quality of spirometry. 

If the quality of spirometry is low, measurements of FEV1 are less 

precise, and it may not be possible to determine if small changes 

are real or artifactual. For employees having spirometry on more 

than one occasion, we investigated changes in lung function over 
Health Hazard Evaluation Report 2008-0155-3131 Page 7

Assessment (continued)

time using spirometry tests of A, B, or C quality. 

As a first approach to investigating lung function changes over 

time, we estimated population average changes in FEV1 and FVC 

as mL/year. Individual values used to calculate these averages 

were determined by linear regression of all the FEV1 and FVC 

values against time for each employee who had spirometry results 

available for more than one point in time. 

As a second approach, we identified individuals with excessive 

changes in FEV1 over time using software developed by NIOSH 

for longitudinal spirometry analysis (SPIROLA) [Hnizdo et al. 

2010]. For individuals with less than 8 years of follow-up, this 

program compares FEV1 values to the limit of longitudinal decline 

(LLD). The LLD is a threshold value used to determine whether 

the lung function decline between the first FEV1 value (or a 

mean of the first two observations, if the first FEV1 value is lower 

than the second one) and each follow-up FEV1 value is excessive. 

Observations that fall below the LLD warrant concern as having 

less than a 5% chance of being normal. Beginning with 8 years of 

follow-up, SPIROLA bases the interpretation of excessive decline 

on an individual’s regression slope and the lower 95% confidence 

limit around the regression line. 

The SPIROLA software adjusts its determination of LLD for 

spirometry quality, as reflected by within-person variation, in 

addition to considering what would be normal declines in healthy 

persons. Unusually high quality spirometry monitoring programs, 

often carried out for research purposes, can achieve a withinperson variation of approximately 3% [Wang and Petsonk, 2004; 

Wang et al. 2006]. We determined that the employees’ spirometry 

data of A, B, and C quality had a within-person variability of 5%. 

We used SPIROLA to identify an LLD of 12.4% longitudinal 

decline based on the relative within-person variation of 5% and a 

referential rate of FEV1 decline of 30 mL/year. 

At the suggestion of the company in an August 2009 letter, we 

repeated the SPIROLA analysis using the American College of 

Occupational and Environmental Medicine (ACOEM) limit of 

longitudinal decline calculated as LLD = (Baseline FEV1× 0.85) 

- (# of years × 30 mL/year), based on 15% longitudinal decline 

and a referential rate of decline of 30 mL/year. This limit requires 

an individual to have greater rate of decline in FEV1 in order 

to be classified as abnormal. Thus, it is more specific but less 
Page 8 Health Hazard Evaluation Report 2008-0155-3131

Assessment (continued)

sensitive for detecting abnormal decline. This more stringent LLD 

is appropriate in settings where spirometry is of relatively poor 

quality. However, because it is not statistically-based, it does not 

adjust the LLD threshold for better quality programs and their 

ability to measure FEV1 with greater precision. 

Associations between work history and lung 

function

An uneven distribution of abnormal medical test results within 

a working population suggests that some areas or jobs may have 

higher risk. We investigated possible associations between lung 

function and the work area variables in two ways. Using logistic 

regression, we modeled the presence of restrictive abnormalities 

based on the most recent spirometry test and having excessive FEV1

decline as categorical variables against work area. Secondly, we used 

analysis of variance models to investigate the association of changes 

in FEV1 and FVC as continuous variables with work area variables. 

Both types of models were adjusted for body mass index of 30 or 

more kilogram/meters2 (obesity or not) at the last test, change in 

weight over the spirometry testing period for each employee (as 

pounds per year), age at last test, smoking as a yes or no categorical 

variable, and tenure in years. For the models using ever worked in 

any one specific area with higher potential for flavoring exposure, 

we used those who never worked in the areas with higher potential 

for exposure to flavoring chemicals as the comparison group. 

Similarly, we compared current employees in any one specific area 

with higher potential for exposure to the employees not currently 

working in areas with higher potential for exposure. 

Exposure assessment

The company completed a form about the frequency of use and 

annual poundage for the 34 flavoring substances on the Flavor 

and Extract Manufacturers Association (FEMA) high priority 

list [FEMA 2004], starter distillate, limonene, nonane, and any 

other chemicals used in large quantities. FEMA had classified 83 

flavoring substances as priorities for consideration as potentially 

posing respiratory hazards in flavoring manufacturing workplaces. 

The priority levels were assigned based on inhalation exposure 

data in animals and humans, chemical structure, and volatility. 

FEMA stated that the 34 substances classified as high priority 

chemicals may pose a risk of respiratory injury when associated 

with high exposure levels, repeated low exposure levels, heating, or 
Health Hazard Evaluation Report 2008-0155-3131 Page 9

Assessment (continued)

inadequate controls. The form also collected information on the 

form (solid, liquid, or paste) of each chemical used and examples of 

product flavors in which the chemical was used. 

We reviewed company reports of air sampling conducted by their 

industrial hygiene consultants between March 2004 and July 2007 

and between July 2008 and August 2009.

During our site visit, we collected 4 air samples for volatile organic 

compound screening, each for about an hour, in the liquid 

compounding, spray dry and dry blend, quality control laboratory, 

and packaging areas. The samples were collected on stainless steel 

thermal desorption tubes containing 3 beds of sorbent material at 

a flow rate of 50 milliliters per minute and analyzed per NIOSH 

Method 2549 [NIOSH 2008] using thermal desorption, gas 

chromatography, and mass spectrometry. These samples do not 

give quantitative measurements, but do provide qualitative results 

which indicate relative abundance of a wide range of compounds 

found in the air. NIOSH investigators typically use this approach 

to collect information to help guide a more in-depth exposure 

assessment. 

Engineering controls

We observed engineering controls (e.g., local exhaust ventilation 

hoods) in several areas throughout the facility during our site visit.

Respiratory protection

Prior to our May 2008 site visit, we received a copy of the 

company’s respiratory protection program documentation. During 

our visit, we interviewed production employees, managers, and 

supervisors about their knowledge and use of respirators, and we 

reviewed 2004-2008 respirator fit-testing records at the contracted 

occupational health clinic. The company sent us a copy of their 

August 2009 respiratory protection program in November 2009.

Hazard communication

During the site visit, we reviewed the written hazard 

communication program and material safety data sheets (MSDSs) 

for two of the company’s diacetyl-containing products. In 

November 2009, we received a copy of the company’s July 2009 

hazard communication program.
Page 10 Health Hazard Evaluation Report 2008-0155-3131

Demographic information

The demographic information for the employees is given in Table 

1.

Work history information

Table 2 shows the number of employees who currently and ever 

worked in each of the areas identified in the company-provided 

information. Extract and distillation was only mentioned as a work 

area for one employee in the past and for none currently. It may 

be that the terminology for that department or area has changed 

over time. There were six employees who had formerly been in 

administration.

Results

Table 1. Demographic characteristics for 112 flavorings 

manufacturing facility employees

Gender (male), n (%) 96 (85.7)

Race, n (%) 

 Caucasian 86 (76.8)

 Black 23 (20.5)

 Hispanic 3 (2.7)

Ever smoked (yes),* n (%) 32 (29.6)

Age in years‡, mean (range) 45.5 (21–67)

Tenure† in years‡, mean (range) 16.2 (0.64–36.1)

Body Mass Index > = 30 kg/m2, n‡ (%) 33 (29.5)

*Smoking status was available for 108 employees.

‡Calculated on date of most recent spirometry test date; for tenure the 

calculation is years from hire date to most recent spirometry test date

†Tenure information available for 95 employees
Health Hazard Evaluation Report 2008-0155-3131 Page 11

Results (continued)

Evaluation of spirometry records 

After we combined all spirometry records provided to NIOSH, 

there were spirometry reports for 112 employees. Table 3 shows the 

number of reports by year of testing and according to spirometry 

test quality. The number of available test results is much greater 

starting in 2004 than earlier. Figure 1 shows the distribution of 

spirometry follow-up time for the 112 employees. This ranged from 

0 months to 11 years. Twenty-eight employees had one spirometry 

test available, and 84 employees had more than one spirometry test 

available. Seventy employees had two or more spirometry tests of 

A, B, or C quality, and 66 of these also had work area information. 

The group of 45 employees with at least two spirometry reports 

who had ever worked in areas of higher potential for flavoring 

exposures had an average follow-up of 5.4 years, in comparison 

to 3.5 years follow-up for the group of 21 employees in areas with 

lower exposure potential. The 28 employees who were currently 

working in areas of higher potential for flavoring exposure had an 

Table 2. Work area distribution of employees with spirometry and 

work history data

Work area Number of 

employees currently

Number of 

employees ever

Administration 0 6

Dry blend* 7 20

Extract and distillation* 0 1

Liquid compounding* 22 47

Maintenance 7 16

Packaging 19 49

Process flavors* 9 16

QC and R&D† 12 20

Sample order 3 3

Spray dry* 4 8

Warehouse 14 27

Total 97

*In our analyses, an area defined as having higher potential for flavoring exposure 

in comparison to other work areas.

†Quality Control and Research Development
Page 12 Health Hazard Evaluation Report 2008-0155-3131

Results (continued)

Table 3. Number and quality of spirometry test reports for 

flavorings manufacturing facility employees by year of testing

Year A-C 

quality D quality

F quality/no quality 

reported or able to 

be created

1998 4 1 3

1999 7 1 0

2000 0 0 0

2001 1 0 0

2002 0 0 0

2003 0 0 0

2004 27 3 0

2005 20 9 0

2006 41 5 0

2007 50 9 1

2008 75 12 4

2009 77 18 1

Totals 302 58 9

28

2

31

1

6

8

19

2 1

14

0

5

10

15

20

25

30

35

0* 0.5-0.9 1-1.9 2-2.9 3-3.9 4-4.9 5-5.9 6-6.9 7-7.9 >= 8

Number of workers

Years of spirometry follow-up

* This indicates having only 1 spirometry test

 Figure 1. Distribution of 112 flavoring manufacturing employees by years of spirometry follow-up.

.
Health Hazard Evaluation Report 2008-0155-3131 Page 13

Results (continued)

average of 5.6 years of follow-up, compared to 4.4 years of followup for the 35 employees with lower current potential for exposure. 

Interpretation of most recent spirometry tests

The most recent test was performed in 2009 for 96 employees, 

in 2008 for 12 employees and between 2004 and 2006 for four 

employees. Forty-eight percent of the most recent spirometry tests 

for each individual had A quality, 14% had B quality, 18% had C 

quality, 18% had D quality, and 2% had F quality. We interpreted 

106 of the 112 tests (90 of A-C quality and 16 of D quality with a 

normal interpretation). We identified 34/106 (32%) employees as 

having abnormal spirometry results. We found a restrictive pattern 

in 30/106 (28%) employees (22 mild abnormality, six moderate 

abnormality, one moderately severe abnormality, and one severe 

abnormality). Additionally, we identified two employees with mild 

obstruction, one employee with moderate obstruction, and one 

with a very severe mixed pattern on their most recent spirometry 

test (Table 4). 

Table 4. NIOSH interpretation of most recent spirometry tests 

from employees at a flavorings manufacturing facility

Interpretation

Employees

N = 106*

n (%)

Normal 72 (68%)

Restricted 30 (28%)

 Mild 22 (21%)

 Moderate 6 (6%)

 Moderately severe 1 (1%)

 Severe 1 (1%)

Obstructed 3 (3%)

 Mild 2 (2%)

 Moderate 1 (1%)

Mixed 1 (1%)

 Very severe 1 (1%)

*Tests were considered interpretable as normal or abnormal if the quality was 

A, B, or C. Additionally, D quality tests achieving values in the normal range 

were interpreted as normal. D quality tests with values in the abnormal range 

were considered uninterpretable because of the possibility that abnormal 

values were due to poor test quality. If a test had an F quality, the test was 

considered uninterpretable. There were 6 such tests.
Page 14 Health Hazard Evaluation Report 2008-0155-3131

Results (continued)

The number of restrictive spirometry abnormalities seen in 

these employees is high. Company employees with spirometry 

measurements had 3.8 times the prevalence of abnormal restriction 

compared to the U.S. population adjusted for age, gender, race, 

ever smoking, and body mass index (prevalence ratio 3.8; 95% 

confidence limit 2.6-5.4). For this analysis, we excluded four 

employees for whom we did not have smoking information.

Changes in lung function over time

Average longitudinal decline of FEV1 and FVC were similar in 

magnitude and larger than would be expected due to aging. As 

calculated using the slopes of the regression of lung function over 

time for A, B, or C quality tests, the mean decline in FEV1 was 

77 mL/year and the mean decline in FVC was 89 mL/year for 

non-smokers (n = 46). For ever smokers (n = 22), these values 

were 109 mL/year for FEV1 and 147 mL/year for FVC. Results 

for percent predicted FEV1 and FVC (which adjust for age) for the 

18 employees tested for all four years from 2006 to 2009 showed 

parallel declines in average percent predicted FEV1 and FVC over 

time with relatively stable FEV1/FVC ratio (Figure 2), consistent 

with a tendency toward restriction. 

78

83

88

93

98

2005 2006 2007 2008 2009

%

% Predicted FVC

% Predicted FEV1

FEV1/FVC

Figure 2. Group means of percent predicted FVC and FEV1 and FEV1/FVC ratio by year of test for 

all A-C quality spirometry tests for 18 employees tested 2006 - 2009. If there was more than 1 test 

per worker in a year, the last test of the year was used.
Health Hazard Evaluation Report 2008-0155-3131 Page 15

Results (continued)

There were 70 employees with two or more spirometry tests of 

A, B, or C quality used in the SPIROLA analyses of abnormal 

declines in FEV1 using criteria for determination of LLD that 

adjusted for 5% within-person variability. Of these 70 employees, 

13 (19%) were identified as having excessive FEV1 declines using 

the 12.4% longitudinal decline criterion. The employee with 

abnormal decline and the shortest period of follow-up (1.9 years) 

lost 499 mL/year, for a total of 900 mL in FEV1. The others with 

abnormal declines in FEV1 had abnormal declines over 4.3 to 

10.7 years with annualized declines of 92-188 mL/year. Of these 

13 employees who had experienced abnormal rates of decline, five 

continued to have FEV1 values in the normal range at their most 

recent spirometry test. These employees may need interventions 

to prevent them from declining further into the abnormal range 

of lung function. We found that 8 (32%) of 25 employees with 

both abnormal restrictive spirometry and serial measurements 

had excessive decline in FEV1, suggesting that the abnormality was 

progressing. 

Using the more stringent value of LLD based on ACOEM 

recommendations, 12 of 70 employees (17%) were identified as 

having excessive FEV1 declines. Five of these employees had a 

normal value of FEV1 at their latest spirometry test.

In summary, 30 employees had restriction on spirometry, three 

had obstruction, and one had a mixed pattern, and an additional 5 

employees had excessive FEV1 declines within the normal range of 

spirometry, for a total of 39 employees (37%) with either abnormal 

spirometry, an excessive decline in FEV1, or both. Only 63% of 

employees had serial spirometry of adequate quality to evaluate 

excessive FEV1 declines, so these proportions of the workforce 

with spirometric findings suggestive of lung disease may be low. 

Use of the 15% ACOEM criterion for excessive decline did not 

substantially change how many individuals were identified as 

having excessive decline in FEV1 compared to use of a statistically 

determined threshold. 

Associations between work history and lung 

function

Since employees in the facility had more abnormalities than 

we expected, both in spirometric restriction and in abnormal 

rapid decline in FEV1, we examined possible work-relatedness 

by examining if employees with higher potential for exposure to 
Page 16 Health Hazard Evaluation Report 2008-0155-3131

Results (continued)

flavorings were more affected.

Restriction on last spirometry showed no significant associations 

with work area. Changes in FEV1 and FVC in mL/year were 

associated (p < 0.05) with ever having worked in areas with higher 

potential for exposure to flavorings. The adjusted means for change 

in FEV1 for ever worked in higher potential exposure areas versus 

never having worked in these areas were -124 mL/year compared 

to -44 mL/year, while for changes in FVC, these values were -144 

mL/year compared to -63 mL/year. Within the category of higher 

potential for exposure, ever having worked in liquid compounding, 

as compared to never having worked in areas with higher potential 

for exposure, was associated with a larger decline in FEV1 (adjusted 

means of -118 mL/year vs. -47 mL/year; p < 0.05). Decline in FVC 

showed a trend for a larger decline for those who had ever worked 

in liquid compounding (adjusted means of -138 mL/year vs. -69 

mL/year; p < 0.1).

Excessive decline in FEV1, defined in comparison to a 12.4% 

longitudinal decline plus a referential decline of 30 mL/year, was 

associated with currently working in higher potential for exposure 

areas (odds ratio = 7.0; 95% confidence interval = 1.3-38.2, p 

< 0.05) and marginally associated with ever working in higher 

potential for exposure areas (odds ratio = 7.5; 95% confidence 

interval = 0.99-56.7, p < 0.1). Consistent results with regard to 

trend were found when excessive decline in FEV1 was defined with 

the ACOEM 15% criteria (Table 5). 

Table 5. Associations between excessive decline in FEV1 and working in areas with higher potential for 

exposure to flavorings*†

Excessive decline criterion

Ever worked in area with 

higher potential for exposure

Odds ratio

(95% confidence limit)

Currently working in area with 

higher potential for exposure 

Odds ratio

(95% confidence limit)

12.4% longitudinal decline 

and referential decline of 30 

mL/year ‡ 7.5 (0.99-56.7)§ 7.0 (1.3-38.2) ¶

15% longitudinal decline 

and referential decline of 30 

mL/year

8.3 (0.99-69.8)§ 6.9 (1.2-40.9) ¶

*Logistic models adjusted for body mass index at time of most recent test equal to or greater than 30 or not, change in 

weight over the spirometry testing period for each employee (as pounds per year), age at last test, smoking as a yes or no 

categorical variable, and tenure in years.

†Summary includes spirometry tests with quality grade of A, B, or C. 

‡This uses the estimated within person variability of 5%.

§p < 0.1

¶p < 0.05
Health Hazard Evaluation Report 2008-0155-3131 Page 17

Results (continued) Exposure assessment

The company reported using 24 of the 34 FEMA high priority 

substances, as well as starter distillate and limonene, and most 

substances were in liquid form. Nine of the 24 were used on a 

frequent basis (Table 6). No information was received for other 

chemicals (not on the FEMA list) used in large quantities.

Table 6. Flavoring substances used in production at flavorings 

manufacturing facility by frequency of use, June 2008*

Flavoring substance Frequency of use†

1 = rarely, 5 = often, 10 = daily

USED FREQUENTLY

Acetaldehyde 9

Acetic acid 9

Acetoin 9

Benzaldehyde 9

Butyric acid 9

Diacetyl 9

Furfural 7

Limonene ‡ 7

Phosphoric acid 9

Propionic acid 7

Starter distillate ‡ 5

USED LESS FREQUENTLY

Ammonium sulfide 2

Ethyl acrylate 1

Formic acid 3

Hydrogen sulfide 1

Isobutyraldehyde 3

Isobutyric acid 3

Methyl mercaptan 3

2-Pentenal 1

Phenol 1

Piperidine 1

Propionaldehyde 3

Pyridine 2

Pyrrolidine 2

Trimethylamine 3

Valeraldehyde 3

* Information received for substances listed on a request form after the site visit. Field 

for “Other ingredients used in large quantities” was left blank. 

†Request form provided the three categorical frequency ranking choices. Company

responded with frequency ranking on a continuous scale between 0 and 10.

‡ All substances in table except these are on the FEMA High Priority Substance 

list [FEMA 2004]. Ten other substances on the list and nonane were not used. 
Page 18 Health Hazard Evaluation Report 2008-0155-3131

Results (continued)

Between March 2004 and July 2007, the facility’s industrial 

hygiene consultants performed four air sampling evaluations at 

the plant when diacetyl-containing products were being prepared 

(Table 7). Sampled analytes included acetaldehyde, acetic acid, 

benzyl alcohol, butyric acid, diacetyl, ethyl acetate, ethyl alcohol, 

phosphoric acid, respirable dust, and total dust. For all substances 

that have occupational exposure guidelines, none were found at 

levels above the guideline limits. NIOSH Method 2557 was used to 

sample for diacetyl in the X-Oil room, liquid compounding, spray 

dry, packaging, and laboratory areas. Diacetyl was found above 

the limit of detection in the X-Oil room, liquid compounding, 

and spray dry, at 8-hour time-weighted average concentrations 

up to 10.2 parts per million (ppm) for area samples and 0.7 ppm 

for personal samples (Table 7). NIOSH Method 2557 has been 

found to be affected by humidity, diacetyl concentration, and time 

to sample extraction [Cox-Ganser et al. 2011], so these results are 

likely underestimates of the true values.

Table 7. Company diacetyl air sampling results using NIOSH Method 2557* from March 2004 to July 

2007

Sample 

Type Location

Number 

of 

samples

Number of 

samples less 

than MDC†

8-hour time-weighted average 

concentration‡ (ppm)§

Minimum Maximum Geometric 

mean¶

Area Laboratory 3 3 < 0.030** < 0.030 < 0.015

Area Liquid compounding 2 1 < 0.028 10.165 0.375

Area Packaging 2 2 < 0.015 < 0.015 < 0.007

Area Spray dry 1 0 0.169 0.169 0.169

Area X-Oil†† 5 1 < 0.033 3.208 0.258

Personal Liquid compounding 4 3 < 0.029 0.260 0.030

Personal Liquid compounding and X-Oil 1 1 < 0.029 < 0.029 < 0.015

Personal Packaging 1 1 < 0.015 < 0.015 < 0.008

Personal Spray dry 2 0 0.056 0.269 0.123

Personal X-Oil†† 1 0 0.762 0.762 0.762

*NIOSH Method 2557 is affected by humidity, diacetyl concentration, and days to sample extraction, so these 

concentrations may be underestimates. 

†MDC = minimum detectable concentration

‡Company results converted to 8-hour time-weighted averages with assumption of no exposure during unsampled periods of 

the shift. 

§ppm = parts diacetyl per million parts air

¶All values less than MDC were replaced with MDC/2 for calculation of geometric means.

**The symbol < indicates concentration was not detectable; value presented is the MDC for minimum–maximums and 

MDC/2 for geometric means.

††Two additional samples (0.89 ppm area, 3.00 ppm personal) were reported without sufficient data (sampling volume and 

time) to calculate 8-hour time-weighted averages.
Health Hazard Evaluation Report 2008-0155-3131 Page 19

Results (continued)

Table 8. Results from thermal desorption tubes collected by NIOSH investigators on May 29, 2008 

Location Sampling 

duration 

(minutes)

Major peaks 

detected*

Surroundings/job activity

Liquid 60 Diacetyl Sample collected approximately 5 feet from a liquid 

compounding station making a lemon emulsion formula 

in the small open area adjacent to the liquid compounding 

room. We did not observe other activities being performed 

during this sampling.

compounding Acetoin

derivatives

Ethyl acetate

Ethyl butyrate

Benzaldehyde

Limonene

Propylene glycol

Trichloroethylene

Spray dry & dry 55 Limonene A dry blend operation was producing a beef savory mix 

with the sample collected approximately 5 feet from the 

mixer. The NIOSH industrial hygienist could not find the 

batch order to identify ingredients.

blend Trichloroethylene

Quality control 53 Ethyl acetate Two laboratory personnel were performing multiple lab 

tests on two separate bench tops. The sample was collected 

on the middle bench located in the middle of the room. We 

did not observe other operations being performed during 

this sampling.

laboratory Ethyl butyrate

Benzaldehyde

Limonene

C10H16 terpenes

Trichloroethylene

Packaging 58 Diacetyl Two production lines were packaging liquid product. We 

observed multiple individuals operating the lines. One 

line was packaging an Orange/Mango product (primary 

ingredients could not be located), and the other product was 

not identified by the NIOSH industrial hygienist.

Ethyl acetate

Ethyl butyrate

Benzaldehyde

Limonene

C10H16 terpenes

Trichloroethylene

*None of the compounds reported in this table were detected on the field blank.

In the limited NIOSH air sampling, diacetyl was found in both 

the liquid compounding and packaging areas (Table 8). Acetoin 

was only seen in liquid compounding. Ethyl acetate, ethyl butyrate, 

benzaldehyde, limonene, C10H16 terpenes, and trichloroethylene 

were identified in most areas sampled. Overall, 61 compounds were 

identified in the four samples.
Page 20 Health Hazard Evaluation Report 2008-0155-3131

Results (continued)

Table 9 presents company results from area and personal air 

sampling for diacetyl from production areas, laboratories, and the 

warehouse on 17 days between July 2008 and August 2009. The 

company reported that the sampling was performed either for 

periodic monitoring or to evaluate effectiveness of engineering 

and administrative controls. The samples were collected using 

Occupational Safety and Health Administration (OSHA) Method 

PV2118 on the first 2 days of sampling and OSHA Method 1012 

on the remainder of sampling days beginning in March 2009. 

All areas sampled had detectable levels of diacetyl, at 8-hour 

Table 9. Company air sampling results using OSHA Methods PV2118 and 1012 from July 2008 to August 

2009

Sample 

Type Location

Number 

of 

samples

Number of 

samples less 

than MDC†

8-hour time-weighted average 

concentration‡ (ppm)§

Minimum Maximum Geometric 

mean¶

Diacetyl Samples 

Area Area 25 2 0 0.073 0.073 0.073

Area Coffee & tea 15 5 0.015†† 0.395 0.076

Area Dry blend 3 0 0.001 0.799 0.008

Area Laboratory 9 4 0.001†† < 0.060** 0.002

Area Liquid compounding 5 1 0.007†† < 0.060 0.014

Area Packaging 7 1 0.001†† < 0.060 0.002

Area Spray dry 5 0 0.042 2.917 0.167

Area Tallow 3 0 0.037 0.042 0.039

Area Warehouse 2 0 0.001 0.002 0.001

Area X-Oil 20 3 0.008†† 0.421 0.055

Personal Coffee & tea 14 6 0.018†† < 0.975 0.155

Personal Coffee & tea / X-Oil 1 0 0.587 0.587 0.587

Personal Dry blend 4 0 0.002 0.219 0.011

Personal Laboratory 9 5 < 0.001 0.027 0.003

Personal Liquid compounding 1 0 1.900 1.900 1.900

Personal Packaging 5 2 0.001†† < 0.118 0.007

Personal Spray dry 3 0 0.076 0.457 0.182

Personal Tallow 1 0 0.892 0.892 0.892

Personal X-Oil 7 1 0.001†† 1.000 0.093

Acetoin Samples

Area X-Oil 2 2 < 0.0002 < 0.060‡ < 0.002

Personal X-Oil 2 0 0.003 0.510 0.036

†MDC = minimum detectable concentration

‡Most company results provided as 8-hour time-weighted average concentrations; when not, company results converted to 

8-hour time-weighted averages with assumption of no exposure during unsampled periods of the shift.

§ppm = parts diacetyl per million parts air

¶All values less than MDC were replaced with MDC/2 for calculation of geometric means.

**The symbol < indicates concentration was not detectable; value presented is the MDC for minimum–maximums and 

MDC/2 for geometric means.

††The value presented was a detectable concentration; other samples in the set were not detectable and had MDCs higher 

than this value.
Health Hazard Evaluation Report 2008-0155-3131 Page 21

Results (continued)

time-weighted average concentrations up to 2.9 ppm for area 

samples and 1.9 ppm for personal samples. The areas with higher 

maximum diacetyl concentrations were in coffee and tea, dry 

blend, spray dry, X-Oil, liquid compounding, and tallow, all of 

which are presumably in the five areas with potentially higher risk 

for exposure that we used in our work-related analyses. The highest 

levels of diacetyl measured in air samples from the laboratory and 

packaging areas were concerning, even though the averages of the 

samples were quite low. Also included in Table 9 are acetoin air 

sampling results; one personal sample measured an 8-hour timeweighted average concentration of 0.51 ppm.

Engineering controls

In 2008, we observed several local exhaust ventilation (LEV) 

hoods during our site visit. These controls included moveable 

exhaust hoods (also known as elephant trunk or snorkel hoods), 

mixing tank ventilation, ribbon blender exhaust, and spray dryer 

packaging exhaust hoods. 

Moveable exhaust hoods were being used in many areas throughout 

the plant, including liquid compounding, dry blend, and spray 

dry. These hoods were often located near bench-top workstations 

on an adjustable arm which allows the employee to position 

the LEV to accommodate varying procedures on the bench. We 

observed a few of these hoods raised to levels that would make 

it difficult for an employee to easily grab and position the hood 

near the process. These hoods provided a flexible mechanism 

to collect contaminants and control exposures. However, their 

effectiveness would have been dramatically affected by cross drafts, 

and capture velocity would drop off quickly as distance increased 

between the contaminant source and the hood face. We also 

observed a number of fans throughout the facility, which was not 

air-conditioned. The fans were reportedly used as a method to cool 

the employees at times of high heat and humidity. However, these 

fans could have disturbed the airflow and dramatically reduced 

the effectiveness of LEV hoods, particularly the moveable exhaust 

hoods. In response to our recommendations concerning LEV hood 

performance, design or operational deficiencies, fan use, cooling 

methods, and negative pressure in production areas, the company 

indicated in their action items that they had made changes 

addressing hood performance and eliminated fans in X-Oil room, 

spray dry, and blending (Table 10). 
Page 22 Health Hazard Evaluation Report 2008-0155-3131

Results (continued)

Table 10. Flavorings manufacturing facility action items as reproduced from August 2009 company response to the interim report 

Item 

No.

Action Item Proposed Action

Estimated 

Completion 

Date

Status

1 Define compliance gaps relative to proposed OSHA Diacetyl standard. Perform gap analysis. 08-Jun-09 Complete. Action items incorporated into this list.2 Develop personnel and area sampling plan and schedule. Design chart to report all results. Develop schedule for sampling in the production, warehouse, QC, SOD, and R&D areas. TBD Sampling phase I completed. Sampling phase II started week of July 13th after improved ventilation in X-oil room, testing of a closed pumping system for pure diacetyl, and implementation of improved procedures.3

Repeat study to define adequacy of local exhaust ventilation in rooms, where diacetyl is transferred.

Conduct test and follow-up on the findings. 17-Jun-09 Testing conducted and all systems confirmed to be operating properly. Certificates posted at all primary ventilation points.

4 Evaluate X-Oil room ventilation. Test & certify air exchanges. 17-Jun-09 Testing conducted and all systems confirmed to be operating properly. Certificates posted at all primary ventilation points.5 Check for negative ventilation in diacetyl use production areas. Obtain smoke tubes and perform tests at interfaces. Determine feasibility of providing negative ventilation. 17-Jun-09 Complete. Floor fans will not be used in areas diacetyl is dispensed. Procedure implemented in X-oil room to discontinue use of fans.6 Define effect of floor fans on ventilation efficiency.

Perform smoke test at dispensing stations with and without fans operating.Develop procedures as needed to ensure adequate ventilation performance.

17-Jun-09

Complete. Floor fans will not be used in areas where diacetyl is dispensed. Procedure implemented in X-oil room to discontinue use of fans. Use of floor/ceiling fans in Spray Dry and Blending will also be discontinued.

7 Develop closed system handling of diacetyl. Modify diacetyl transfer equipment and procedures to minimize potential exposure during diacetyl transfers. 24-Jun-09 Pump system currently being tested to achieve a closed dispensing system. Plan to develop a complete dispensing, receiving, mixing system, if sampling results show need.8 Define current handling procedures for diacetyl in the labs. Labs report use, quantity, and dispensing methods. 22-Jun-09 Complete. All lab staff using ventilation systems and hoods. Procedures updated to reflect proposed OSHA standard and personnel trained on the procedure.9 Evaluate adequacy of respirators currently used. Contact supplier for protection factor and assess level of protection. Complete analysis when the sampling program is implemented. 16-Jun-09 Complete. Pre-filters added. The respirators provide protection superior to what the most stringent requirement in the proposed OSHA standard.

10 Enhance current Respiratory Protection Program.

Identify hazardous chemicals requiring respiratory protection.Identify type of respirator and cartridge for each chemical.Add specific list of chemical and respirator needed into the existing program.

11-Jun-09 Complete.

11 Respiratory protection during formulation process. Change procedure to wear respirator during full weighing cycle. Obtain chronological test data for exposures after weighing. 23-Jun-09 31-Jul-09 Complete. Implemented procedural change for respirator use. IH sample results to be evaluated. A second survey is planned in September to confirm the first set of results. 

12 Evaluate spill response procedures.

Review existing procedures and revise to include handling of spills by emergency response with appropriate PPE (Tyvek suits, butyl gloves) and disposal of contaminated materials.

16-Jun-09

Completed procedure review. New standard communicated to first responder personnel. The procedure will be revised and communicated to all personnel by mid-September.

13 Establish cleaning procedures to minimize airborne diacetyl. Initiate use of cold water for cleaning. 12-Jun-09 Complete.14

Health hazard training on diacetyl for employees.Health warnings on MSDS and labels.

Develop training materials, incorporate into existing Hazcom and Respiratory Protection programs. Continue to update MSDS.Train employees annually.

18-Jun-09 Complete. MSDS’s health hazards are updated/entered as they are reviewed/developed.
Health Hazard Evaluation Report 2008-0155-3131 Page 23

Results (continued) Item No. Action Item Proposed Action Estimated Completion Date Status 15 Use of engineering control ventilation by production employees. Develop training material, train all personnel, and document training. 31-Jul-09 Complete. Training completed for manufacturing. The total diacetyl handling procedure (which includes this particular item) will be reviewed with both manufacturing and R&D per action item 28. 16 Use OSHA methods 1012 & 1013 for IH testing. Have IH consultant use OSHA methods. 09-Mar-09 Complete. 17 Substitutes for diacetyl. Define possible means of removing diacetyl and substitutes for future formulations. TBD Policy implemented to avoid diacetyl in new formulations wherever possible. 18 Hazcom training specific to diacetyl. Develop training module. 18-Jun-09 Complete.

19

Enhance recordkeeping - Medical form consistent with proposed OSHA standard.

Develop form containing employee work history, spirometry testing results, employee communications, etc. 22-Jun-09 Complete.

20 Make the December 2003 NIOSH Alert available to all employees. Determine best means of accomplishing or if past practices have met the equivalency of doing so. 24-Jun-09 Complete. Past practice was probably sufficient but now enhanced.21 Evaluate addition order of diacetyl containing batches. Determine if diacetyl can be the last component added to a batch to minimize total potential exposure period. 07-Jul-09 Complete.22

Conduct communication session on diacetyl and IH issues with all employees.

Communicate proposed new OSHA standard and steps taken by company to be in full compliance. 20-Jul-09 Complete.

23 Evaluate need for refrigerated storage with closed dispensing system. Determine vapor pressure at various storage temperatures. Analyze likely effect of storage temperature change on personnel exposures. 07-Jul-09 Complete. Procedure implemented to refrigerate diacetyl until used.24 Review monitoring data collected during 

June and July.

Conduct meeting to analyze data to date and formulate an action plan to address findings. 05-Aug-09

Complete. No issues in packaging, SOD, and R&D relative to most conservative proposed OSHA permissible exposure limit of 50 ppb. Closed pumping system in X-oil room successful in reducing exposure levels to well below 50 ppb. Spray Dry, Reactions, and Liquid Compounding areas will be studied further.

25

Repeat study to confirm positive impact of the closed pumping system in the X-oil room.

Conduct a second round of testing with the new pump system to see whether positive results from first test can be duplicated. 15-Sep-09

26 Monitor Spray Dry, Reactions, and Liquid Compounding areas. Schedule IH survey under controlled processing conditions to define sources of exposure and evaluate options for containment. 21-Sep-09

The study will include investigation of the transfer process, the operating conditions (temperature, pressure), and any other relevant factors that may contribute to higher concentrations. This evaluation will pinpoint the sources and define the means of mitigation/elimination.

27

Summarize data to date and action plan going forward and communicate to site employees.

Develop chart with a summary of current results by area. The chart will reflect averages and range of results. 28-Aug-09

28

Complete training for all site personnel on handling procedures, which fully incorporate specifics in the proposed OSHA standard.

Finalize procedures and schedule training for all site personnel. 30-Sep-09

Table 10. (continued)
Page 24 Health Hazard Evaluation Report 2008-0155-3131

Results (continued)

Regarding our interim report recommendation to take precautions 

similar to those for diacetyl if diacetyl substitutes are used, the 

company implemented a policy to avoid diacetyl and substitutes 

in new product formulations whenever possible (Table 10). 

Additionally, they were going to determine, when diacetyl is used, 

if it could be added as the last component of the batch to minimize 

potential for exposure to diacetyl.

The company initiated cold water cleaning and cold storage of 

diacetyl per our recommendations. Table 10 also indicates that 

they successfully developed a closed dispensing system in the X-Oil 

room with reduction in diacetyl exposure levels. Further study was 

planned for installation in other areas such as spray dry and liquid 

compounding. 

Respiratory protection 

Fifty-three employees with information from 2007 and/or 2008 

had been medically cleared to wear respirators. 

Although the initial respiratory protection program documentation 

received prior to our visit covered respirator maintenance, 

selection, inspection, and use in the workplace, it did not include 

clear guidelines on when to wear respirators. Our interim report 

included a recommendation that a list of chemicals and their 

corresponding respirator selection and filter/cartridge selection 

criteria be incorporated into the written respiratory protection 

program so that employees understand exactly when and for what 

chemicals respiratory protection is required. The August 2009 

respiratory protection program documentation included, in its 

table of respiratory equipment used at the facility, the addition 

of full-face respirators with organic vapor and particulate filter 

cartridges for use when dispensing diacetyl. However, the table 

included descriptions of other respirators without information on 

the associated hazardous chemicals or job titles and tasks for which 

that respirator should be worn. 

During our site visit, we noticed that production batch tickets 

indicated the need for respiratory protection for some chemicals 

during the first use of the chemical in the process, but there was 

no indication of the need for respiratory protection for those same 

chemicals on subsequent batch tickets. We also observed that only 

the employee working directly with a chemical wore respiratory 

protection while an employee in close proximity did not. The 
Health Hazard Evaluation Report 2008-0155-3131 Page 25

Results (continued)

action items prepared by the company in 2009 (Table 10) indicated 

that the recommendation in our interim report to require 

respiratory protection in downstream batches was incorporated 

into the full weighing cycle, and air sampling results would be 

evaluated to determine the downstream need after weighing. 

An action item in response to our recommendation to require 

respiratory protection for employees in close proximity to exposed 

employees was not included. 

In response to our interim report recommendation that employees 

wear respirators and eye and skin protection when cleaning spills 

or washing empty containers of flavoring chemicals, an action item 

in Table 10 indicated that the company would prepare a revised 

procedure to include handling of spills by emergency response 

personnel with appropriate personal protective equipment.

Hazard communication 

The two MSDSs we reviewed during our site visit for diacetylcontaining products referred to the “December 2003 NIOSH 

Report” (presumably the December 2003 NIOSH Alert, 

“Preventing Lung Disease in Employees Who Use or Make 

Flavorings”) on the occurrence of severe lung disease in 

employees who make or use flavorings. In our interim report, we 

recommended that the company make the NIOSH Alert available 

to their medical provider and their own employees. The company’s 

action items in Table 10 indicate that although they considered 

their past practice as sufficient, they enhanced it. Regarding 

our other recommendations for communication of diacetyl and 

diacetyl substitute health hazard information to its employees, the 

company’s action items indicate they developed a diacetyl training 

module for presentation in annual training sessions. Information 

in the training sessions was to include health hazards, air sampling 

results, company action items, proper use of LEV hoods and 

respirators, and flavoring handling procedures. 

Discussion The additional spirometry screening results provided by the 

company after our June 2009 interim letter were consistent with 

our previous findings: Its employees had nearly four times the 

prevalence of spirometric restriction than the general United 

States population, after adjusting for contributing factors such as 

overweight and obesity. Eight of the 25 employees with spirometric 
Page 26 Health Hazard Evaluation Report 2008-0155-3131

DDisccussion (ccontinued ontinued)

restriction and serial spirometry measurements had abnormal 

declines of spirometry measured over time, consistent with 

progressive loss during employment. The statistical associations 

that we have documented between abnormal declines in lung 

function and jobs with high potential for flavorings exposures 

suggest employment exposures may be causing deterioration 

in lung health. The finding that 37% of employees had either 

abnormal spirometry or abnormal declines in spirometry or both 

is concerning. Putting in place a program that identifies employees 

who have abnormal rates of decline in spirometry on serial 

testing but still have normal FEV1 and FVC values may offer the 

opportunity to intervene early and preserve normal lung function.

The analyses presented here suggest that these abnormal rates 

of lung function decline are related to workplace exposures. The 

evidence in favor of work-relatedness is three-fold: First, employees 

with higher potential for flavorings exposure in their work areas 

had 2.8 times greater annualized decline in FEV1 than employees 

in jobs with lower potential for exposure, and the average yearly 

decline was about 4 times greater than is normal in the general 

population (124 versus 30 ml/year). Second, employees with 

current higher potential for flavorings exposure had 7 times the 

risk of abnormal decline in FEV1 compared to employees with 

lower potential for exposure. Because employees often relocate 

to other jobs if they have or suspect health effects related to their 

work (“healthy worker effect”), we evaluated whether employees 

who had ever worked in areas with higher potential for flavorings 

exposure had higher risk compared to employees who had never 

worked in areas with higher potential for exposure and found 

even higher risk than was associated with current employment in 

potential high exposure jobs. Finally, within the higher potential 

for flavorings exposure work areas, we could demonstrate that 

a single job group, those ever working in liquid compounding, 

had statistically increased annual FEV1 decline in comparison 

to employees who never worked in areas with higher potential 

flavorings exposures. With these three types of evidence for 

excessive deterioration in pulmonary function associated with 

employment in areas with high potential for flavorings exposure, 

the company needs to aggressively intervene to assure that its 

employees are protected from potentially harmful exposures. 

We do not think that the absence of a statistical association 

between restrictive abnormality and work areas with higher 

potential for flavorings exposure is evidence against a work-related 
Health Hazard Evaluation Report 2008-0155-3131 Page 27

Discussion (continued)

excess of restriction. The employees referred for spirometric testing 

were all thought to have potential for flavorings exposure, which 

is documented in the diacetyl measurements available from the 

company’s 2009 sampling. Thus, the 3.8-fold excess of restriction 

in the employee population undergoing surveillance compared to 

the general population was broadly distributed between areas that 

we thought had higher potential for flavorings exposure and areas 

that had lower potential for flavorings exposure. The maximum 

diacetyl exposures documented in some of the employees working 

in lower potential for exposure areas were high enough to have 

caused lung disease in microwave popcorn plant employees 

[Kanwal et al. 2006]. We do not know that diacetyl is the cause of 

the lung disease in this company’s flavoring employees. Cases of 

flavoring-related lung disease in microwave popcorn employees 

suggests that a susceptible subpopulation exists that develops 

disease within months and at relatively low exposures compared to 

mixers [Akpinar-Elci et al. 2004; Kreiss et al. 2002].

Understandably, both the company and medical contractor were 

concerned by the potential respiratory hazard of diacetyl. These 

concerns were evident in the efforts of the company to decrease 

diacetyl exposure through respiratory protection, changes in work 

practices, substitution of diacetyl by other chemicals, and education 

of employees about specifics that had been proposed for inclusion 

in a possible Occupational Safety and Health Administration 

standard for diacetyl (Table 10). 

However, flavoring companies have many chemical exposures 

other than diacetyl. Thus, even though restrictive spirometric 

abnormalities are not normally thought to be a result of diacetyl 

exposure, our evidence of increased burden of restriction in 

the work force, accelerated rate of FEV1 decline, and statistical 

associations between this decline and work history should 

motivate additional efforts to evaluate potential causes and control 

potentially causative exposures. 

The first step should be to determine the nature of the restrictive 

spirometric abnormalities seen in nearly one-third of employees 

with usable spirometry. As indicated above, restriction may reflect 

obesity, but we adjusted for body mass index in both comparisons 

with the U.S. population and in models of excess risk by job 

indices of exposure. We also adjusted for change in weight over 

the spirometry intervals in looking at the declines in FEV1, which 

paralleled the declines in FVC, as would be expected in evolving 
Page 28 Health Hazard Evaluation Report 2008-0155-3131

Discussion (continued)

restrictive abnormalities. Another cause of spirometric restriction 

is neuromuscular weakness, but this seems an unlikely cause in 

a production employee population. Poor quality spirometry with 

insufficient inhalation before forced expiration or insufficient 

exhalation time and effort can result in apparent restrictive 

abnormalities, but we limited our analyses to spirometry with 

adequate repeatability within test sessions. Despite our care in 

evaluating the data, it is certainly possible that some individual 

employees may have had these non-pulmonary causes of a 

restrictive spirometric pattern. However, our analysis suggests that 

most of the restrictive abnormalities documented in the work force 

are not due to obesity or artifacts related to poor test quality.

Instead, we are concerned that these changes in spirometry 

may reflect underlying scarring or inflammatory (interstitial) 

occupational lung disease in a substantial fraction of company 

employees with abnormal spirometry. Additional diagnostic tests 

other than spirometry are needed to establish the proportion of 

employees with restrictive spirometry that have low lung volumes 

or other evidence of interstitial lung disease. The predictive value 

of a restrictive pattern of spirometry for low lung volumes in a 

population of patients referred to a hospital pulmonary function 

laboratory was 58% [Aaron et al. 1999]. The prevalence rate of true 

restriction documented by lung volume testing might be higher 

in the company’s employees, given their common exposures that 

might be a cause of restrictive lung disease. Still, without medical 

testing in addition to spirometry, we cannot be sure whether 

spirometric restriction reflects lung disease. It should be noted 

that in a case series of patients with documented restrictive lung 

diseases, the combination of restrictive spirometry and low total 

lung capacity were quite insensitive [Boros et al. 2004]. Thus, if 

true restrictive lung disease is shown to exist in some employees 

with restrictive spirometry, all employees may need to have other 

diagnostic tests performed to assess for interstitial lung disease. 

All employees with abnormal current spirometry (including 

restrictive, obstructive, and mixed abnormalities) or excessive 

declines in FEV1 need evaluation with further medical tests by 

an appropriate specialist with expertise in occupational and 

pulmonary medicine who is knowledgeable about this report 

and its findings. Steps for follow up evaluation of those with 

restrictive spirometric abnormalities might include confirming 

restriction by measuring lung volumes; evaluating gas transport 

by measuring carbon monoxide diffusing capacity; testing for 
Health Hazard Evaluation Report 2008-0155-3131 Page 29

Discussion (continued)

exercise-induced oxygen desaturation; and evaluation with sensitive 

imaging studies such as high resolution computerized tomography 

scanning. For those with obstructive abnormalities, steps for 

follow up evaluation might include evaluating for spirometric 

bronchodilator response, measuring lung volumes to assess for 

air trapping, ruling out emphysematous or interstitial changes by 

measuring carbon monoxide diffusing capacity, and evaluation of 

paired inspiratory and expiratory high resolution computerized 

tomography scans for evidence of air trapping. Evaluating the 10 

employees with moderate to very severe spirometric abnormalities 

first may be particularly informative about potential disease 

processes and could guide subsequent diagnostic evaluation of 

those with mild abnormalities. Specialist attention might also be 

useful in evaluating for excessive spirometric decline on an ongoing 

basis, using the information to intervene early to reduce potential 

workplace exposures while employees still have relatively normal 

lung function. 

Restrictive abnormalities have previously been documented among 

flavoring-exposed employees in other work settings. Although 

diacetyl and flavoring exposures are well known to have caused 

crippling lung disease due to fixed obstruction and bronchiolitis 

obliterans in the microwave popcorn and flavoring manufacturing 

industries, the full spectrum of lung diseases related to flavoring 

exposures remains unclear [Kreiss 2007a]. A case of restrictive lung 

disease without a nonoccupational explanation has been reported 

among former employees in the index microwave popcorn plant 

[Akpinar-Elci et al. 2004]. Cases of restriction were present early in 

the investigation [Kreiss et al. 2002] and evolved during follow-up 

[NIOSH 2006]. Restriction has also been noted in other microwave 

popcorn plants [NIOSH 2003]. In flavoring manufacturing 

employees in California, there were more employees with restrictive 

than with obstructive spirometric abnormalities [Kim et al. 2010]. 

One case report documents restrictive spirometry in a food 

production plant worker who used flavorings. He was found to 

have bronchiolitis obliterans with organizing pneumonia [Alleman 

and Darcy 2002]. In another report, 4 of 22 food production 

plant workers had spirometric restriction. None of the 22 had 

obstruction [Day et al. 2011]. Thus, while the significance of 

restrictive lung disease among flavorings-exposed workers remains 

uncertain, current medical literature suggests that it may be within 

the spectrum of health effects related to flavorings exposure.
Page 30 Health Hazard Evaluation Report 2008-0155-3131

Discussion (continued)

The current report documents an excess of employees with 

restrictive spirometry and an association between longitudinal 

loss of lung function and employment in certain job categories. 

The finding that abnormal loss of lung function is not uniformly 

distributed among company employees and is concentrated 

among employees with higher potential for flavoring exposures 

is consistent with a work-related cause. To understand what 

is causing these abnormalities and how to address them, the 

company’s medical contractor needs access to employees’ further 

diagnostic tests. Company referral of workers needing in-depth 

evaluations to a small group of expert medical consultants might 

facilitate rapid recognition of disease patterns so that the spectrum 

of flavoring-related disease can be established. Similarly, physicians 

conducting ongoing medical surveillance should have access to job, 

area, and task information so that they can recognize epidemiologic 

patterns of abnormalities and their distribution in the employee 

population, facilitating recognition of work-related adverse health 

effects and ongoing targeting of prevention efforts.

Because symptoms of respiratory disease may not be reported by 

employees, medical surveillance including spirometry is essential 

to protecting employees’ health. The company should work with 

its medical provider to establish a formal medical monitoring 

and surveillance program. The California Department of Public 

Health, with assistance from NIOSH, developed guidelines for 

medical surveillance for flavoring-related lung disease among 

flavoring manufacturing employees [California 2007]. The 

guidelines recommend that once an employee is identified as 

having a flavoring-related lung disease, employees whose jobs 

pose similar or greater risk should undergo spirometry testing 

every 3 months. In this facility, there is both excess spirometric 

restriction compared to the general population and evidence of 

work-related excessive decline in FEV1. Although the nature of 

these abnormalities is unclear, we recommend testing at 3-month 

intervals until the nature of the excessive FEV1 declines among 

production employees is understood and abnormal declines 

stabilize following lowered exposures. More frequent testing 

provides an opportunity for the medical provider to improve 

spirometry quality, which is critical for early ascertainment of 

excessive declines. In World Trade Center responder medical 

surveillance, the criterion for adequate technician performance is 

that 80% of employees achieve A or B quality spirometry [Enright 

et al. 2010]. In fact, even 90% of ill patients can achieve A or B 

quality spirometry with adequate coaching [Enright et al. 2004]. In 
Health Hazard Evaluation Report 2008-0155-3131 Page 31

Discussion (continued)

comparison, the medical contractor providing spirometry to this 

company achieved 62% A or B quality on company employees. 

Suboptimal quality (including C, D, and F quality) spirometry 

should be repeated within a month. The company might consider 

withholding payment for spirometry testing in which quality 

criteria are not met. 

There are several limitations in our evaluation of this plant. 

First, 19% of the spirometry records provided by the company’s 

medical provider were of D or F quality, and an additional 18 % 

had C quality, indicating marginal repeatability of measurements 

within a test session. High quality spirometry testing improves the 

ability to detect relationships between exposures and employees’ 

lung function, particularly in evaluating declines over time. Our 

evaluation of serial spirometry records may have underestimated 

abnormal declines because we excluded poor quality spirometry, 

and only 70 employees had serial tests with A, B, or C quality. 

The work history information provided by the company was 

less detailed than we would have collected from direct employee 

interviews to identify high-risk tasks associated with job titles. Data 

analysis was based on limited observations of the various processes 

performed at this facility, and few exposure measurements were 

available to support our classification of some areas as having 

higher potential for flavoring exposures than the remainder of jobs 

and areas. These limitations may have resulted in misclassification 

of exposures and health outcomes, either of which would lower our 

ability to detect possible work-related associations. For example, 

we did not include laboratory, research and development and 

quality control, and packaging employees in the group with higher 

potential for exposure, although this classification would be 

appropriate in some other plants that we have visited.

Unavailability of quantitative exposure characterization for 

employees in various work areas over time prevented us from 

doing more sophisticated statistical analyses concerning the 

relationship between cumulative or average exposure estimates 

from a job-exposure matrix linked to work history and lung 

function abnormalities. Representative exposure assessments 

in flavorings plants are difficult because of the wide diversity in 

batch operations and recipes. On our walk through of the plant, 

the NIOSH industrial hygienist and engineer collected only four 

air samples on the second shift for an hour or less. These few 

samples were not intended to be representative of workplace 

exposures overall. NIOSH did not have relative humidity, 
Page 32 Health Hazard Evaluation Report 2008-0155-3131

Discussion (continued)

temperature, and days to extraction with which to correct company 

air sampling data collected between March 2004 and July 2007 

using NIOSH Method 2557, which is known to be affected by 

absolute humidity and time to extraction of sampling media. The 

company air sampling data provided to NIOSH following our site 

visit was collected using OSHA sampling methods that require 

no adjustment. Although we could not construct a job-exposure 

matrix over time with the available company data, the more recent 

company measurements provided some evidence that the areas that 

we considered to have higher potential for flavoring exposures had 

higher diacetyl measurements. No measurements were available for 

extract and distillation, which had no current employee and only 

one past employee. 

A final limitation is the small numbers of employees in many 

production categories. Small numbers limit statistical power 

to determine differences among subgroups. We were able 

to demonstrate that employees who ever worked in liquid 

compounding had significantly greater declines in FEV1 compared 

to employees who had never worked in areas with high potential 

for exposures to flavorings. This statistical finding does not imply 

that employees in other areas within the group of higher potential 

exposure areas had no risk, but whatever risk they might have 

could not be detected with the numbers of employees. We were not 

able to demonstrate that restrictive abnormalities were associated 

with working in an area with higher potential for exposure. 

Whether this was the result of inadequate power to detect a 

difference, misclassification of exposure or health response, or 

no association cannot be determined. However, the constellation 

of excessive restrictive spirometry in the whole population, workrelated excessive FEV1

 decline, and uncertainty about the levels 

of safe exposures to an unknown causal agent(s) present in this 

workplace present cause for concern and justify measures to 

assure that potential respiratory health problems are recognized, 

characterized, and prevented. 
Health Hazard Evaluation Report 2008-0155-3131 Page 33

The findings from our spirometry record review indicate that 

the flavorings manufacturing facility employees who underwent 

spirometry testing at the contracted clinic had 3.8 times greater 

prevalence of spirometric restriction than the U.S. population after 

adjusting for age, gender, race, smoking, and body mass index. 

About one-third of employees had spirometric abnormalities, 

most of them restrictive in nature. Furthermore, even using 

the conservative criteria recommended by ACOEM, 17% of 

the employees with adequate longitudinal spirometry data 

had abnormal declines in FEV1 over time. Statistical modeling 

indicated that abnormal decline in FEV1 and that annualized 

average decreases in FEV1 and FVC were associated with working 

in areas with higher potential for exposure to flavoring chemicals. 

Employees who had ever done liquid processing had greater average 

annualized falls in spirometric measurements than employees who 

had never worked in an area with higher potential for flavoring 

exposure. These results suggest that the flavorings company 

employees are experiencing respiratory health effects related to 

ongoing exposures in the workplace. Further medical testing of 

those with abnormalities in spirometry is warranted to define any 

lung diseases resulting in restrictive spirometric abnormality in 

this workplace. Frequent follow-up of those with excessive FEV1

decline may assist in documenting that workplace interventions to 

lower flavoring exposure are effective in preventing work-associated 

declines in lung function. 

Conclusions

Recommendations

Based on observations and findings from our initial site visit 

and subsequent documentation we received, we encourage the 

company to continue to use the recommendations provided in 

our interim report. Following are additional recommendations; 

some may appear to repeat those previously provided because we 

lack information on the status of action items, or to emphasize the 

importance of continuing consideration:

Substitution and engineering controls

1. Until inhalation toxicity information is available on 

diacetyl substitutes such as acetoin, 2,3-pentanedione, 2,3-

hexanedione, 2,3-heptanedione, starter distillate (which 

contains diacetyl), and diacetyl trimer (which decomposes 

to diacetyl), the same precautions needed to prevent diacetyl 

exposure need to be taken for these substitutes.
Page 34 Health Hazard Evaluation Report 2008-0155-3131

Recommendations

(continued) 2. The local exhaust ventilation hoods should be evaluated 

periodically to assess their performance and to identify any 

design or operational deficiencies. 

3. Continue to avoid use of floor fans in the vicinity of hooded 

processes, as the floor fans could disturb the airflow and 

dramatically reduce the effectiveness of local exhaust hoods,

particularly the moveable exhaust hoods.

4. Continue to keep production areas where flavors are 

compounded under lower room air pressure than adjacent 

areas. This reduces the escape of flavoring chemicals and 

potential exposure to other areas.

Respiratory protection

5. A list of chemicals and their corresponding respirator and 

filter/cartridge selection criteria should be incorporated 

into the written respiratory protection program. Specific 

guidance is necessary for employees to understand exactly 

what chemicals and tasks pose exposure hazards, which 

employees are at risk, and what respirator will provide 

adequate protection.

6. Batch tickets should reflect the need to wear appropriate 

respiratory protection throughout the flavor formulation 

process, regardless of the process step. Although use of 

respiratory protection was extended to weighing tasks, as 

well as during the first use of the chemical, downstream 

exposures to intermediate mixtures of chemicals during 

subsequent batch tickets may also require respiratory 

protection. 

7. Because chemicals such as diacetyl are volatile and can easily 

migrate from one location to other nearby locations, nearby 

employees should employ proper respirators. 

8. Continue to have employees wear personal protection 

equipment including: (1) respirators that provide protection 

against both organic vapors and particulates and (2) eye and 

skin protection when cleaning up spills or washing empty 

containers of flavoring chemicals or ingredients. 

Hazard communication / employee education

9. Because the plant manufactures food flavorings, the 

company should make copies of the December 2003 
Health Hazard Evaluation Report 2008-0155-3131 Page 35

Recommendations

(continued) “NIOSH Alert: Preventing lung disease in employees who 

use or make flavorings” available to their medical provider 

and to their own employees.

10. The company should continue updating its MSDSs 

with information on diacetyl health hazards and means 

of protection, and providing respiratory protection 

guidelines on production batch labels. We also encourage 

the company to keep their training module up to date 

on the health hazards of and protection from flavoring 

chemicals (including diacetyl). These should comply with 

OSHA Hazard Communication guidance for diacetyl and 

other flavoring ingredients (http://www.osha.gov/dsg/

guidance/diacetyl-guidance.html). If diacetyl substitutes are 

introduced, we suggest that the MSDSs, training, respiratory 

protection, and work practices incorporate similar protective 

measures because the respiratory toxicity of diacetyl 

substitutes remains unclear.

11. Continue to ensure that employees are trained on how to 

use the local exhaust ventilation hoods properly; provide 

guidance on proper usage and good work practices.

12.Continue to keep containers of flavoring chemicals and/

or ingredients sealed when not in use, and use cold water 

washes and cold storage of chemicals when feasible. 

 

Medical screening and surveillance

13.The company should work together with its medical 

provider to establish a formal medical monitoring and 

surveillance program. This program should include 

ascertainment of symptoms and spirometry testing of 

lung function for all employees with potentially hazardous 

exposure to flavorings or flavoring ingredients prior to job 

placement and then every 3 months. Since high quality 

spirometry is critical to determining excessive declines 

in FEV1, the company might consider incentives to its 

contractor to achieve the highest quality spirometry possible. 

When the company has evidence that excessive declines 

in lung function in the workforce have resolved with good 

quality serial spirometry, the interval for assessment of 

symptoms and spirometry testing of exposed employees 

can be increased to every 6 months. The monitoring and 

surveillance program should identify cases of lung function 

abnormalities among flavorings-exposed employees, 

establish baseline measurements for new employees, and 
Page 36 Health Hazard Evaluation Report 2008-0155-3131

Recommendations

(continued) track changes in lung function over time to detect any rapid 

or excessive decline in lung function. NIOSH SPIROLA 

software is available without cost to assist in tracking 

abnormal declines in spirometry. Detecting abnormal 

declines in lung function is essential to prevent employees 

from suffering harm which may be irreversible. Those with 

abnormalities in spirometry or excessive interval declines 

in FEV1 should be evaluated further for diagnosis and 

appropriate management, considered for work restriction 

from further flavoring exposure, and followed at 3 month 

intervals until stable.

The company’s contract with its medical provider should 

provide for aggregate epidemiologic analysis of the 

medical results, including analysis of medical results by 

department or job. Aggregate analysis can identify hazards 

associated with flavoring manufacture and may assist the 

company with data-driven priorities for prevention through 

exposure control. Medical results considered in aggregate 

analyses should include both the results of the medical 

monitoring and surveillance program; and the results of 

any in-depth medical evaluations resulting from abnormal 

findings identified by the monitoring and surveillance 

program. Company referral of employees needing in-depth 

evaluations to a small group of expert medical consultants 

might facilitate rapid recognition and reporting of disease 

patterns suggesting emerging workforce health problems. 

Exposure assessment

14. For air sampling, continue to use OSHA Methods 1012 and

1013 to measure diacetyl in the air (http://www.osha.gov/

dts/sltc/methods/validated/1012/1012.html and http://

www.osha.gov/dts/sltc/methods/validated/1013/1013.

html). Routine measurements should be made to ensure 

continued engineering control effectiveness in preventing 

diacetyl exposures. Additional measurements should 

be obtained following changes in processes or controls 

that could affect exposures to diacetyl. In the absence of 

regulated permissible exposure limits, flavoring exposures 

should be as low as possible, since health-protective 

exposures may be lower than analytic limits of detection. 
Health Hazard Evaluation Report 2008-0155-3131 Page 37

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Acknowledgements and

Availability of Report The Respiratory Disease Hazard Evaluation and Technical 

Assistance Program (RDHETAP) of NIOSH conducts field 

investigations of possible health hazards in the workplace. These 

investigations are conducted under the authority of Section 20(a)

(6) of the Occupational Safety and Health (OSH) Act of 1970, 29 

U.S.C. 669(a)(6), or Section 501(a)(11) of the Federal Mine Safety 

and Health Act of 1977, 30 U.S.C. 951(a)(11), which authorizes 

the Secretary of Health and Human Services, following a written 

request from any employers or authorized representative of 

employees, to determine whether any substance normally found 

in the place of employment has potentially toxic effects in such 

concentrations as used or found.

RDHETAP also provides, upon request, technical and consultative 

assistance to federal, state, and local agencies; labor; industry; and 

other groups or individuals to control occupational health hazards 

and to prevent related trauma and disease. 

Mention of any company or product does not constitute 

endorsement by NIOSH. In addition, citations to websites 

external to NIOSH do not constitute NIOSH endorsement of 

the sponsoring organizations or their programs or products. 

Furthermore, NIOSH is not responsible for the content of these 

websites. All Web addresses referenced in this document were 

accessible as of the publication date.

This report was prepared by Kay Kreiss, Jean Cox-Ganser, and 

Chris Piacitelli of RDHETAP, Division of Respiratory Disease 

Studies. Field site visit was conducted by Yulia Iossifova, Nancy 

Sahakian, James Couch, and Kevin H. Dunn. Data management 

and programming was provided by Brian Tift, Kathy Fedan, Nicole 

Edwards, and Carrie Thomas. Pulmonary function interpretation 

was aided by Paul Enright, M.D. Desktop publishing was 

performed by Tia McClelland.

Copies of this report have been sent to management 

representatives at the facility, HHE requestor (local branch of 

the International Brotherhood of Teamsters), the Indiana State 

Department of Health, and the OSHA Region 5 Office. This 

report is not copyrighted and may be freely reproduced. The report 

may be viewed and printed from the following internet address: 

http://www.cdc.gov/niosh/hhe. Copies may be purchased from 

the National Technical Information Service (NTIS) at 5825 Port 

Royal Road, Springfield, Virginia 22161. 
Below is a recommended citation for this report:

NIOSH [2011]. Health Hazard Evaluation Report: Lung Function (Spirometry) 

Testing in Employees at a Flavorings Manufacturing Plant --- Indiana. U.S. 

Department of Health and Human Services, Public Health Service, Centers for 

Disease Control and Prevention, National Institutute for Occupational Safety and 

Health, NIOSH HETA No. 2008-0155-3131.

To receive NIOSH documents or information about 

occupational safety and health topics contact NIOSH at:

1-800-35-NIOSH (1-800-356-4674)

Fax: 1-513-533-8573

E-mail: pubstaft@cdc.gov

or visit the NIOSH web site at:

http://www.cdc.gov/niosh/hhe

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