TECHNICAL REPORT 

Respiratory and Immunologic 

Evaluation of Isocyanate 

Exposure in a New 

Manufacturing Plant 

U.S. DEPARTMENT OF HEAL TH AND HUMAN SERVICES 

Public Health Service 

Centers for Disease Control 

National Institute for Occupational Safety and Health 
Respiratory and Immunologic Evaluation 

of Isocyanate Exposure in a New 

Manufacturing Plant 

Hans Weill, M.D. 

Brian Butcher, Ph.D. 

Venkatram Dharmarajan, Ph.D. 

Henry Glindmeyer, D.Eng. 

Robert Jones, M.D. 

Jean Carr, M.S.H. 

Carol O'Neil, M.S. 

John Salvaggio, M.D. 

Tulane University School of Medicine 

New Orleans, Louisiana 

NIOSH Contract No. 210-75-0006 

U.S . DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

Centers for Disease Control 

National Institute for Occupational Safety and Health 

Division of Respiratory Disease Studies 

Morgantown, West Virginia 

June 1981 

Few •ale by the Superintendent of Document"•, U .S. Government 

Printing_ Office , Washiniiton, D .C. 20402 
DISCLAIMER 

Mention of company names or products does not constitute 

endorsement by the National Institute for Occupational Safety 

and Health. 

NIOSH Project Officer: James A. Merchant, M.D., Dr. P.H. 

Principal Investigator: Hans Weill, M.D. 

DHHS (NIOSH) Publication No. 81-125 

if 
ABSTRACT 

In April, 1973, pre-exposure (baseline) information was obtained on 

168 workers who were to begin manufacturing toluene diisocyanate (TDI) in 

four months. None of these workers had prior exposure to TDI. Subsequent 

follow-up in this longitudinal investigation was five and one-half years in 

length, during which time eight additional visits were made to· the manufacturing site. At each of visits 2, 3, 4 and 5, approximately 25 participants 

were added to the study population, bringing the total size of the study 

population to 277 . The added participants had no more than 11 months of 

TDI exposure prior to inclusion in the study. 

Exposure to TDI vapor was determined by personal monitors utilizing 

the paper tape stain method for continuous 8-hour measurement . The approximately 2,000 personal samples collected had median 8- hour time-weighted averages of .002 ppm. The 25th and 75th percentiles were .0011 and . 0036 respectively. Percentage of time above . 02 ppm, the current threshold limit value , 

averaged 3% in these personal samples. All members of the study population 

had some degree of TDI exposure, which depended on both job and location. 

No systematic trends in exposure were observed over the course of the study . 

Detailed job histories allowed for the construction of cumulative 

exposure as a product of concentration and time. Cumulative exposure was 

used to define two exposure categories (division point= . 0682 ppm-months) 

with the low category chosen to represent the exposure received by a worker 

who spent the full follow-up period in a group of jobs (median 8- hour timeweighted average~ .0011 ppm) with the lowest TDI concentration. 

Pulmonary function annual changes for spirometric measurements, lung 

volumes and diffusing capacities were computed for each participant as the 

slope of the least squares straight line using time as the independent 

variable . 

The average annual decline of FEV1 was 24 ml per year , comparable to 

that expected on the basis of cross sectional studies of "normal" populations. 

Average annual declines of FEF25_75 and FEF50 were 93 and 110 ml, larger than 

expected on the bas.is of cross sectional data. Average annual declines for 

single breath. carbon monoxide diffusing capacity and the diffusion constant 

(K) were also larger than expected on the basis of cross sectional results. 

After controlling for pack years of smoking and atopic status, FEV1 , 

FEV% and FEF2s- 75 annual declines were significantly related to the TDI 

·exposure categories. Lung volume and diffusing capacity annual change was 

not related to TDI exposure. 

iii 
The effect of TDI exposure on FEV1 annual change was manifest 

primarily in those who never smoked cigarettes; its effect in smokers may 

be masked by smoking. In the never smokers·, there was a 38 ml per year 

(p = .001) difference between the low and liigh exposure categories. Among 

current smokers there was· no observed effect of TDT. In the low exposure 

category, there was a 27 ml per year (p = • 004) difference oetween never 

and current cigarette smokers-. This· difference is comparable to the effect 

of TDI in the never smokers-. Current smokers averaged 18 pack years of 

smoking. Never smokers in the low exposure group had an average annual 

increase in FEV1 of 1 ml per year. 

TDI exposure as determined by cumulative dose and peak exposure as 

measured by time spent above 0.02 ppm correlated equally well with annual 

change in pulmonary function. 

Clinically important bronchial hypersensitivity to TD!' developed in 

4.3% of the study population. A number of these workers were shown to develop 

bronchoconstriction in the laooratory following inhalation challenge using a 

maximum concentration of 0.02 ppm TDT. Half of the TDI reactors had been 

exposed to high_ levels during a spill or equipment -mal:Eunction. 75% of the 

reactors b.ecame symptomatic wi.thin seven -months of firs·t exposure to TDI. 

Some TDI reactors have failed to attain pre-exposure or pre ... sensitization 

values of FEV1 or FEF25-75 despite transfer to other areas of the chemical 

complex. Neither atopy nor smoking served to identify persons at higher risk 

of developing TDI reactivity. 

TDI at certain concentrations acts as a partial agonist on lymphocytes 

to stimulate cyclic adenosine monophosphate (AMP) levels. At lower concentrations, it can block cyclic AMP stimulation by isoproterenol and prostaglandin E1 but not histamine. Lymphocytes of TDT sensitive individuals have 

decreased ability to respond to cyclic AMP stimuli such as beta agonists, 

isoproterenol, prostaglandin E1 and TDT. 

RAST with p-tolyl isocyanate conjugated to human serum albumin only 

detects tolyl specificlgE antibodies in the serum of 15-18% of subjects 

proven by provocative inhalation challenge to be TDI reactive. This demonstrates that the presence of tolyl specific serum tgE antibodies cannot be 

used to diagnose clinical sensitivity to TDI. 

All other humoral or cellular indicators of immunologic sensitization 

were non-revealing. 

iv 
I. 

II. 

III. 

IV. 

v. 

TABLE OF CONTENTS 

Introduction 

Study Design and Protocols 

TD! Exposure Indices 

A. 

B. 

C. 

Cumulative Exposures 

Time Above • 02 PPM 

Assignment of Exposure Indices for 

Correlation Studies 

Longitudinal Results and Analysis 

A. 

B. 

c. 

D. 

E. 

Introduction 

Spirometry Results 

Diffusion and Long Volume 

Respiratory Symptoms 

Immunology 

F. Detail~d Analysis of FEV1 Slope 

TD! Reactors 

A. 

B. 

c. 

D. 

E. 

F. 

G. 

Clinical and Epidemiologic Features 

Immunologic Findings 

Provocative Inhalation Challenge with TDI 

Challenge Testing with Methacholine Chloride 

(Mecholyl) 

Study of the Effect of Pretreatment with 

Disodium Cromoglycate 

Lymphocyte Transformation and Leukocyte 

Histamine Release 

Lymphocyte cAMP Dose Response Studies 

V 

Page Number 

1 

3 

8 

9 

11 

11 

12 

12 

15 

20 

20 

23 

23 

29 

29 

30 

31 

31 

32 

32 

32 
v. 

VI. 

H. 

I. 

J. 

K. 

L. 

TABLE OF CONTENTS 

(Continued) 

Plasma Histamine Levels 

Determination of Serum Complement and 

Split Products of Complement 

Loss of TD! and Methacholine Reactivity 

after Removal from Isocyanate Exposure 

Concurrent Development of Food Allergy and 

Isocyanate Reactivity 

Tolyl-specific IgE Antibodies in Serum 

of TD! Reactive Individuals 

Conclusions 

Appendix 1 - Environmental Characterization 

Appendix 2 - Statistical Considerations 

Appendix 3 - Interview Forms, Symptom Criteria 

References 

Tables 

Figures 

Reprints 

and Editorial Programs 

vi 

Page Number 

33 

33 

34 

34 

34 

36 

39 

48 

59 

94 

98 

130 

152 
I. INTRODUCTION 

The construction of a new plant in Southwestern Louisiana for 

production of toluene diisocyanate (TD!) with start of operation late in 

1973 led to a proposal by the National Institute of Occupational Safety 

and Health (NIOSH) to the investigators for a longitudinal study of respiratory health of the workers who would be exposed to TDI. The ability to 

begin the study prior to the start of TDI production presented the unique 

opportunity of obtaining pre-exposure biologic data on the study population. The proposed investigation had the full agreement and cooperation of 

the major chemical company operating this plant and its labor representatives. 

It has been known for two decades that reversible airways obstruction develops in a small proportion of workers exposed to isocyanate vapors, 

either during manufacture or application processes. In addition to the 

recognition of the risk for developing this form of occupational asthma, 

there had been a suggestion that chronic progressive fixed airways obstruction was detected in an exposed population and was not related to "sensitivity", but rather was a general effect of TD! exposure. 

This multi-disciplinary investigation addressed the following 

scientific questions: 

(1) What are the characteristics of plant airborne TDI concentrations, particularly in terms of average exposures, as well as variation 

in short term concentrations (peaks)? This was first assessed by area monitoring using a physico-chemical method for continuous monitoring developed 

in the United Kingdom and introduced into this investigation by the principal 

investigator resulting in its first research or other application in the 

United States. During the course of the contract, personal sampling for continuous airborne concentrations of TDI vapor was similarly initiated and 

formed the basis for the comprehensive personal exposure profiles in these 

manufacturing workers detailed in this report. 

(2) What proportion of exposed workers become reactive to TD! 

vapor following exposure, what are the temporal relationships between initial 

exposure and such reactivity, and what are the clinical manifestations in 

the reactive group? 

(3) Are there host factors which will serve to identify those 

~ndividuals who are susceptible to TDI exposure and develop the clinical 

picture of occupational asthma as the result of such exposure? 

1 
(4) Can the phy~iologic consequences (bronchoconstriction) of 

e...xposure in susceptible workers be reproduced in the laocratc~J by brcnchcprovocation; and what are the physiologic, immunologic and exposure characteristics of such a reproduced bronchoconstrictor response? 

(5) What is the mechanism of TD! induced asthma? Is it immunologic or non-i1I1TJ1unologic? 

(6) Is there a generalized adverse effect on respiratory function 

in the exposed working popuiation, and if so, what are its determinants 

(e.g., host factors, level of exposure)? 

(7) Is the airways obstruction which results from development of 

TD! reactivity reversible in all instances, or are there permanent residual 

effects which are measurable by follow-up serial ventilatory function studies? 

If permanent changes occur in some reactive individuals, what are the determinants of such irreversibility? 

(8) Does development of TD! reactivity lead to a general (nonspecific) bronchial hyperresponsiveness? 

(9) What are the dose-response relationships of any acute or 

chronic respiratory effects identified in this exposed population as determined either by the longitudinal field survey or bronchoprovocation testing? 

(10) Are there levels of exposure which are not associated with 

any acute or chronic adverse respiratory health effects? 

(11) Are there measurements, either physiologic, immunologic or 

other which are likely to be useful in identifying workers who may have a high 

risk of developing TD! reactivity prior to or during the course of their exposure? 

(12) What is the course of specific and non-specific bronchial 

hyperresponsiveness following removal of the susceptible worker from exposure? 

As the reader of this report will appreciate, considerable information impacting on the above questions has been obtained in this five-year 

investigation. However, our knowledge concerning TDI-induced respiratory 

health effects is by no means complete and several issues require additional 

scientific inquiry for their resolution. 

2 
II. STUDY DESIGN AND PROTOCOLS 

As originally conceived, the study design sought to compare three 

TDI exposure categories with respect to the longitudinal course of respiratory symptoms, spirometric measurements, lung volumes and diffusing capacity. 

Initial measurements were made prior to TDI production (and exposure) enabling an individual to serve as his/her own control. The three exposure categories were (1) TDI production workers in daily contact with the chemical, 

(2) workers (primarily maintenance personnel) with intermittent TDI contact, 

and (3) controls employed outside the TDI production area. In April of 1973, 

prior to the beginning of TDI production, 168 workers were administered a 

modified British Medical Research Council questionnaire. It was used to 

gather smoking histories and to determine presence or absence of (1) upper 

respiratory symptoms, (2) lower respiratory symptoms, and (3) bronchitis 

(see longitudinal symptom analysis section for definitions). In addition, 

the 168 individuals underwent spirometric testing and determination of lung 

volumes and diffusing capacities. 

Of the original 168 participants, 49 had left the plant (two died 

and 47 either were fired or laid off, retired, quit, or transferred away 

from the plant) by the last visit in October of 1978. This corresponds to 

a dropout rate of 4.22% per visit. In addition to the 49 participants of 

the original 168 who had left the plant by the last visit, 19 refused to perform forced expiratioRs at the last visit. The decrease from 168 to 100 

participants at the final visit corresponds to a dropout rate of 6.28% per 

visit. 

The manufacturing site was visited a second time in November, 1973, 

at which time pre- and post-shift spirometric testing was performed. No 

relationship between pre- and post-shift decline and TDI exposure was observed. 

Subsequent visits have totaled 7: September, 1974 (spirometry, lung volumes, 

and diffusion); March, 1975 (spirometry); October, 1975 (spirometry, lung 

volumes, and diffusion); March, 1976 (spirometry); November, 1976, December, 

1977 (spirometry, lung volumes, and diffusion); and October, 1978 (spirometry 

and lung volumes). A respiratory health questionnaire was administered at 

each of the follow-up visits. Change in symptom status was assessed by comparing the initial visit status with that on the last available questionnaire 

provided it was administered at one of the last three visits. 

As the follow-up period lengthened, the original exposure categories lost their integrity due to job changing by participants. Concurrently, detailed exposure information based on personal monitors became 

available allowing the original exposure categories to be replaced by cumulative exposure in ppm-months. (See the environmental section below.) 

3 
At each of visits two through five approximately 25 participants 

were added to the study population. At their entry point, the interview used 

at the initial April, 1973, visit was administered. The additions brought 

the total size of the study population to 277. In contrast to the original 

168 participants who had no prior TD! exposure, the added participants had 

been exposed to TD! for a short period of time prior to their entry into the 

All had prior exposure less than 11 months. 

Table I presents summary data, by visit, on spirometry participation for the 277 participants in the data file. Completing the interview 

seems better accepted by the workers than spirometric testing, and there are 

individuals with completed interviews who refused to perform forced expirations. Thus, Table I underestimates interview participation. 

In the Fall of 1976, due to the continuing erosion of the study 

population because of workers leaving the plant, it was decided to follow 

up those who had left in order to see if their health had changed since 

leaving the plant. There were 42 people who had left the plant at that time 

and of those, 17 were successfully tested. The remainder were either impossible to locate or unwilling to be tested. The results of this follow-up 

were reported in the annual report of 1977. 

All participants were tested with a subset of 16 common inhalant 

allergens*. The presence of two or more positive prick tests (wheal diameter 

1 mm greater than control) was used . to define atopy. 

A copy of the initial and follow-up interviews together with the 

criteria used to define respiratory symptom categories can be found in 

Appendix 3. Also presented is a listing of the computer programs used to 

edit the interviews. Each coded interview has been machine edited to check 

for missing data and.logical inconsistencies. When possible, errors were 

corrected. This procedure resulted in complete interview information for 

98.5 percent of the 277 initial interviews. 

There are several factors which impact on accuracy and reliability 

of pulmonary function measurements. They are instrumentation, calculation, 

data reduction methods, instrument calibration, test procedures and technician variability. These factors are now discussed in turn. 

Pulmonary function tests were conducted in a mobile laboratory on 

a Cardio-Pulmonary instrument (Model 5000) Pulmolab. This unit is capable 

of measuring expiratory flows and volumes, lung volumes, and single breath 

diffusing capacity. It is ·equipped with an electronic dry rolling-seal 

spirometer which provides BTPS outputs of all volumes and flows. During a 

*Allergens used were those known to be of local clinical relevance and 

included Aspergillus sp., Homodendrum sp., Fusarium sp., Bermuda grass, 

Johnson grass, Helminthosporium sp., Alternarea sp., white oak, giant 

ragweed mix, elm, pecan, house dust, marsh elder, cat dander, dog dander, 

and plantain. 

4 
maximum forced expiration, the output is fed into an XYT recorder in order 

to obtain plots of flow vs volume or volume vs time. The parameters calculated from the forced expiration include the forced vital capacity (FVC), 

the forced expiratory volume in 0.5 and 1.0 seconds (FEV0 5 and FEV1), the 

FEV1/FVC ratio reported as a percent, the forced expiratory flow beEween 25 

and 75% of the FVC (FEF2~ 75), FEF50 and FEF25 • All these parameters were 

measured for each indiviaual who was available at the time of testing. However, only satisfactory data were used in the analysis. For spirometry to be 

satisfactory for an individual, the two largest FVC maneuvers must be within 

3% of one another. In addition, these curves must have a sharp initial flow 

with a smooth continuous effort extending until either flow plateaus to 0.0 

liters per second, or seven seconds have elapsed. Therefore, the FVC could 

be termed an FEV7. When there are more than two satisfactory curves, all 

data from the two maneuvers with the highest combined percent of predicted 

for FEV 5 and FEF25_

75 were stored for analysis and averaged. These two 

parameters should provide data with the largest initial effort indicated by 

the high FEV 5 and a good sustained effort, indicated by the large FEF25_75 • 

The only change in calculation procedures occurred in 1975 when backward 

extrapolation was introduced to determine zero time for the beginning of timed 

volume (YEV 5, FEV1). At that time, all data previously calculated were 

recalculated using this procedure and the data file was updated so that all 

data for the entire course of the study was standardized with a backward 

extrapolation start of time. 

The measurement of lung volumes included the slow vital capacity 

maneuver (VC) and the residual volume (RV) measured by the nitrogen washout 

technique. In addition, the alveolar volume (AV) is taken as the sum of 

inspired volume from the diffusion test and residual volume. The total lung 

capacity (TLC) is calculated as the sum of RV and the larger of VC or FVC. 

The diffusing capacity for carbon monoxide in units of milliliters per minute 

per millimeter of mercury was measured by the single brea!~ meth~1 (DLC05B). 

The diffusion constant K equals DLCO /AV in units of min mmHg • For 

measurements of residual volume and aiffusing capacity only satisfactory data 

were analyzed. For satisfactory data, the residual volume from two tests 

had to be within 10% of each other, or 200 cc, whichever is larger. The 

smallest RV was used in the analysis. The diffusing capacity is reported 

from two DLCO measurements within 10% of each other in which the alveolar 

volume is at least 85% of the total lung capacity and the time for the test 

is within ten to fourteen seconds. 

In 1978, a computerized data reduction system was connected on line 

to the Pulmolab. The output from the Pulmolab is instantaneously fed by means 

of a ten bit A/D converter to a Datapoint 1100 computer processor with three 

diskette drives. Data resolution of the computer are 10 ml for volume and 

. 20 ml/sec for flow. The computer calculates the parameters listed previously 

and uses the method of backward extrapolation in determining the FEV 5 and 

FEV1 • These outputs are immediately displayed for the technician on"a cathode 

ray tube, and if the tests are considered satisfactory by the technician, the 

5 
data are reduced in the same method previously employed when data were 

calculated by hand. The reduced data is stored magnetically on diskettes. 

In order to insure that this computerized system did not systematically 

affect data collection, spirometry obtained on 100 individuals was calculated by hand and compared to that measured by the computerized system. 

The mean difference between hand and computer calculated values were within 

1% and 2% of the observed volumes and flows, respectively. 

In addition to measuring spirometric parameters, the computer also 

determines residual volumes and diffusion capacity. These data were calculated and reduced with the same methods previously employed. In addition, 

when values obtained by computer were compared to those obtained by previous 

methods, identical data were produced. 

The volume accuracy of the spirometer is calibrated with a 1,000 ml 

syringe, and time calibrated with a stop watch. Setting the test gas cylinders at constant pressure would produce a constant flow into the spirometer. 

This will produce a linear plot of volume versus time, and repeating the 

maneuver gives a flow versus volume plot. If flow is accurately measured, 

its amplitude would equal the slope of the volume time plot (volume and time 

having been previously calibrated). The calibration for volume, time and 

flow was conducted twice daily and adjustments made if the volume inaccuracy 

exceeded 10 ml, flow inaccuracy exceeded 50 ml per second, or the time inaccuracy exceeded 1%. 

The accuracy of the gas analyzers for measuring DLCOSB was assessed 

with a gas mixing pump which precisely mixed measured gas volumes-to+ .06% 

accuracy. Simple combinations of test gases and room air provided by-this 

gas mixing pump were used to assess accuracy and linearity of the analyzers. 

If linearity changed more than 1%, new linearity curves were employed. Though 

this measurement was conducted monthly, changes in linearity occurred no more 

than once per year. Accuracy and span for the gas analyzers were conducted 

twice daily. This was done to determine the instrument's ability to measure 

0% gas, and 100% gas for a diffusion mixture consisting of .3% CO and 10% 

helium in air. (Note: 100% CO gas would be .3% CO). These were adjusted 

twice daily if the concentrations varied by more than 1%. In addition, the 

technicians conducting the tests were tested weekly to insure repeatability 

of the diffusion measurements. In no case did the week to week variation 

differ by more than 2%. In addition, following the technicians over a long 

term, that is, more than one year, never produced variations greater than 3% 

in single breath diffusing capacity. 

The nitrogen analyzer used in the measure~ent of residual volume by 

the multibreath washout method was checked for O, span, and linearity at 

least twice daily. This was conducted by injecting 100% oxygen across the 

system, 80% nitrogen, or by washing out a canister of room air and displaying 

6 
a semi log plot of nitrogen versus volume. A linear decline of this plot 

implies that there was no leak in the overall circuitry and plumbing of the 

system, and that the analyzer produced a linear response throughout the span 

of Oto 80% nitrogen. This test was conducted twice daily and adjustments 

were made if the volume inaccuracy from the washout was greater than 20 ml, 

or if the O or span inaccuracy was greater than 1%. If there was a problem 

in linearity it was always corrected before testing was conducted. 

Test procedures remained the same for the duration of the study. 

All subjects were tested for spirometry in the standing position. Nose 

clips were used for all tests. The closed circuit procedure was used for 

spirometry, that is, the subject inspired from the spirometer and then 

expired the maximum forced vital capacity into the spirometer. In this way, 

the inspiration preceding the forced vital capacity could be monitored in 

order to assess the subject's ability to reach total lung capacity. At least 

four forced vital capacity measurements were conducted on each subject. At 

least two were displayed as volume/time curves and two as flow/volume loops. 

The lung volume and the diffusing capacity tests were always conducted in the 

seated position. Again, nose clips were always used, and at least two measures of residual volume were conducted which had to be within 10% or 200 ml, 

whichever is larger. The smallest residual volume measurement was used in 

analyses. At least three single breath diffusing capacity tests were conducted on each subject and of those, the two chosen for analyses had to be 

within 10% of one another. If more than two were within 10%, the two with 

the largest alveolar volume, alveolar volume being the sum of inspired volume 

plus residual volume; were used in analyses. In addition, the time duration 

for diffusing capacity had to be within 10 to 14 seconds, and the alveolar 

volume had to be at least 85% of the total lung capacity. 

Technician variability was held to a minimum by always having two 

technicians conduct the tests. The technicians used in the field always 

had at least two years of in-house pulmonary function testing in our laboratories. In addition, each technician was supervised for at least four on 

site field studies by a bioengineer OiWG) '6.efore being allowed to conduct 

independent testing. 

As a final precaution, once data was entered into the computer for 

analysis, a sample of that data was printed to insure that the correct information was coded with the correct individual and stored for analysis in the 

appropriate format for the data base. In this way, the raw data and the 

reduced data were checked for agreement prior to analysis. 

In summary, pulmonary function measurements were conducted throughout the study using the same equipment and test procedures. The method of 

backward extrapolation was implemented after the initiation of the study, but 

past data were recalculated and the analysis updated. In addition, the implementation of a computerized data reduction system was carefully analyzed 

7 
and proved comparable to previous methods of data reduction and calculation. 

Therefore, for the duration of the study, data collection was standardized 

to reduce ~ariability. Every precaution possible was taken to insure that 

the changes seen in this population during the duration of the study were 

influenced as little as possible by the random and systematic variability 

which often affects measurements of pulmonary function. 

The complete data file from all nine visits contains information on 

277 participants. Four of these are female and have been deleted from all 

analyses. Table 2 presents descriptive statistics on the 274 males in the 

study. 85% of them are white, 73.7% are current (51.1%) or ex (22.6%) cigarette smokers, and 20.1% reacted positively to two or more skin tests. They 

have a mean age of 35.9 years, a mean height of 69.9 inches, and averaged 

14.4 pack-years of cigarette smoking. All pulmonary function percent predicteds were near 100% with the exception of FEF25_ 75 (91.0%). 

Each subject's chect x-rays held by the plant medical department 

were reviewed by a physician (RNJ) in 1974. The purpose was to detect 

potentially confounding disorders (e.g., tuberculosis, fibrosis) and to be 

certain that these were neither unusually prevalent nor unevenly distributed 

among groups of participants. Only a few subjects had films suspicious for 

inactive granulomatous infection; only one subject had diffuse linear shadows 

suggesting interstitial fibrosis, and the abnormality was stable, and long 

antedated TD! exposure. After this systematic review, an individual's later 

films were examined only if the investigators learned that he or she was having persistent or recurrent symptoms, or requested review of the films. No 

abnormal films were detected by individual case review. Review of reasons 

for absence due to illness in a 12-month period failed to detect cases of 

recurrent pneumonia, but recorded diagnostic information was often incomplete. 

In the entire study .period we detected no case with clinical or radiographic 

evidence suggesting hypersensitivity pneumonia. 

III. TD! EXPOSURE INDICES 

Two thousand and ninety three personal samples on 143 workers were 

collected using MCM type 4000 tape samplers and 4100 MCM integrating Reader 

Recorder System, bo~h manufactured by Universal Environmental Instruments 

and supplied by MDA. Scientific Incorporated of Park Ridge, Illinois. Sampling was done in a relatively uniform manner with respect to time from June, 

1975, through October, 1978. All job categories in the TD! manufacturing 

area are represented in the 143 people monitored. 

Appendix 1 

program and Appendix 

exposure categories. 

and the two exposure 

details the technical aspects of the TD! monitoring 

2 treats the statistical methodology us·ed to define 

In this section, the environmental data are sunnnarized 

indices developed for each participant are described. 

8 
A. Cumulative Exposure 

One hundred and forty four of the 2,093 personal samples were 

taken by maintenance workers during a single one-month period in 1975 (called 

turnaround time) of concentrated maintenance activity. Since these maintenance workers were not a representative collection of maintenance workers and 

since no sampling was done during subsequent turnaround times (the wearing of 

monitors was an impediment to work performance), these 144 samples were not 

used to determine cumulative exposure categories. 

Since the frequency distribution of the 8-hour time-weighted averages of the remaining 1,949 samples, representing 42 job titles, was markedly 

skewed to the right, they were transformed using logarithms to the base 10. 

The frequency distribution of the transformed 8-hour time-weighted averages 

9 
was approximately symmetrical and the following categories were defined 

on the log scale: 

Category 

1 

2 

3 

4 

5 

6 

7 

8 

TWA1 

lower limit 

0 

.00025 

.0005 

.001 

.002 

.004 

.008 

.016 

upper limit 

.00025 

.0005 

.001 

.002 

.004 

.008 

.016 

.032 

LOG (TWA) 

lower limit upper limit 

-4.00 -3.60 

-3.60 -3.30 

-3.30 -3.00 

-3.00 -2.70 

-2. 70 -2.40 

-2.40 -2.10 

-2.10 -1.80 

-1.80 -1.50 

(If LOG (TWA) coincided with a category boundary, it was placed 

in the lower category.) 

Figure 1 contains histograms of the 1949 8-hour time-weighted averages used to develop exposure categories and of the 144 "turnaround time" 

8-hour time-weighted averages. Table 3 contains descriptive statistics for 

the same two sets of 8-hour time-weighted averages. 

Using clustering techniques described in Appendix 2, the 42 job titles 

as described by 1949 8-hour time-weighted averages were divided into three 

categories: HIGH, MODERATE, and LOW. The jobs which make up each category are 

listed in Table 4. The jobs cluster by exposure as follows: 

(1) TDI C-Operators and Drununing E-Operators in the HIGH GROUP 

(2) TDI Foreman, TDI B-Operators, TDI maintenance personnel, and 

the TDI Laboratory Samplers in the MODERATE GROUP, and 

(3) Primarily non-TDI area located jobs in the LOW GROUP. 

Histograms on the LOG (TWA) scale and descriptive statistics in ppm 

for each of three exposure categories are presented in Figure 2 and Table 5 

respectively. The histograms provide graphic verification of the separation 

between the HIGH and LOW GROUPS (80% of the samples in the LOW GROUP fall in 

LOG (TWA) category 4 or lower whereas 80% of the samples in the HIGH GROUP 

fall in LOG (TWA) category 5 or higher.) with the MODERATE GROUP lying in an 

intermediate position. The descriptive statistics in ppm show that the 25th 

percentile, the median, the geometric mean, tne mean, and the 75th percentile 

1TWA - 8-hour time-weighted average 

10 
all increase approximately by multiples of two from the LOW to HIGH CATEGORY, 

thus establishing a definite exposure gradient. 

Job histories collected from personnel records and interviews were 

used to determine the number of months a participant spent in each of the 

three exposure categories. Cumulative exposure in ppm-months was computed by 

multiplying the time in an exposure category by a representative measure of 

concentration for that category and then summing the three obtained products. 

The representative measure of concentration was taken to be the geometric 

mean of the observed 8 hour time weighted averages for the category. The 

geometric mean instead of arithmetic mean was used as a measure of central tendency since it is more representative of the central portion of the distribution when, as is the case here, positive skewness is removed by taken logarithms. 

B. Time Above .02 ppm 

In addition to calculating the 8-hour time-weighted average 

from each personal sample, the length of time the concentration was above 

each of the levels .005, .01, .02, .04, .06, and .08 ppm was recorded. This 

information on the 2,093 samples representing 50 job titles was used to 

develop "peak exposure" categories as described in Appendix 2. The job 

titles for each of the resulting categories are listed in Table 6. The 

proportion of time spent above each level is presented in Table 7 by category. 

Using individual job histories, the time spent above a particular 

concentration level was calculated as the sum over peak exposure categories 

of the product of time spent in the category and proportion of time spent 

above the level for that category. This quantity whose units is months was 

used in seeking associations between health effects and peak exposure. This 

index is not equal to the actual time above a particular level but is only 

proportional to it. The constant of proportionality (approximately .25) 

adjusts for the· fact that in a 30 day or 720 hour month, approximately 168 

hours are spent in the workplace. 

Although six indices of peak exposure, one for each concentration 

level, were calculated, they were so highly correlated (the smallest correlation coefficient was .96) that we have used only the time above .02 ppm in the 

health effects correlation analyses. Because of its high correlation with 

the other five indices, no new information would be obtained by substituting 

the other indices for time above .02 ppm. 

c. Assignment of Exposure Indices for Correlation Studies 

Four different sets of statistical analyses, one each for spirometry, lung volumes, diffusion, and respiratory symptoms are presented in the 

11 
following sections. Since the visits for which usable data is available 

is different for each four analyses, exposure indices have been computed 

separately for each. Thus, for example, the cumulative exposure and time 

above .02 ppm indices for spirometry were computed from time of initial 

exposure at the manufacturing site through the date of the last visit for 

which usable spirometric data on the participant is available. In a 

similar manner, the two exposure indices were computed for each participant 

for each of the three other analyses. 

In addition to treating cumulative exposure and time above .02 ppm 

as continuous variables as defined above, cumulative exposure and time above 

.02 ppm categories were also developed for use in relating a health effect 

to exposure. One of these categorizations dichotomized the continuous 

exposure index and the other created three subgroups as described below. 

F~r cumulative exposure GROUP I consists of those participants 

whose cumulative exposure (for a particular analysis) was less than or 

equal to .0682 ppm-months and GROUP II those participants with more than 

.0682 ppm-months of exposure. To create three cumulative exposure categories, GROUP II was further dichotomized into GROUP !IA AND GROUP IIB 

using a division point of 0.1 ppm-months. 0.0682 ppm-months= (0.0011 ppm) 

X (62 months) was chosen as the first division point because it corresponds 

to the exposure accumulated by a participant who spent 62 months, the time 

from initial TD! production to the end of the study, in the lowest concentration exposure category which has a geometric mean of 0.0011 ppm. This 

placed approximately two-thirds of the population into GROUP I. The division 

point to dichotomize GROUP II into GROUP IIA and IIB was chosen so as to 

result in approximately equal numb.ers in these two subgroups. 

For time above 0.02 ppm GROUP I consists of those participants who 

spent no longer than 0.19 months above 0.02 ppm and GROUP II those participants with exposure longer than 0.19 months above .02 ppm. This division 

point corresponds to the time spent above 0.02 ppm for a participant who 

spent the full period of 62 months in the lowest peak exposure category. 

GROUP I determined in this way contained approximately two-thirds of the 

study population. To create three peak exposure categories, GROUP II was 

further subdivided into GROUP !IA and GROUP IIB of approximately equal 

numbers using a division point of one month. 

IV. LONGITUDINAL RESULTS AND ANALYSIS 

A. Introduction 

The overall objective of this longitudinal study has been to 

relate change in variables representative of health status to host factors 

12 
and variables reflecting exposure to TDI. The health status variables 

considered in the longitudinal analysis are spirometric measurements: 

FEVi, FVC, FEV%, FEF2s-75, FEF50; diffusion capacity DLco and K; 

lung volumes: RV, TLC, and (RV/TLC) X 100; and respiratory symptoms: 

upper respiratory symptoms, lower respiratory symptoms; bronchitis and 

dyspnea. The host factors considered are cigarette smoking as measured 

by pack-years and atopic status as defined in the section on study design 

and protocols. TDI exposure indices as defined in the section on environmental characterization have been based on cumulative exposure and time 

above .02 ppm. 

Each of the health status variab.les with the exception of respiratory symptoms are quantitative in nature and annual change for them has been 

computed as the slope of the least squares straight line using time since 

initial visit as the independent variable. Usable data from three or more 

visits was sufficient to include a participant in the analysis. The slopes 

or annual changes were regressed using the technique described in Appendix 2 

on independent variables representing TDI exposure, atopic status, and 

cigarette smoking. For each of the pulmonary function measurements six 

regressions were performed. In each regression pack years of cigarette smoking and atopic status as represented by a dummy variable equal to 1 if the 

participant was atopic and O otherwise, were included in the independent 

variables. The coefficient of the variable representing atopic status is an 

estimate of the mean annual change in atopics minus the mean annual change 

in non-atopics after controlling for the other variables. The variables 

representing exposure to TDI in the six regres·sions are as follows: 

Regression 1 

Regression 2 

Regression 3 

Cumulative exposure in ppm-months. 

A dummy variable called cumulative exposure category II 

which is 1 if cumulative exposure is greater than .0682 

ppm-months (See the Environmental Characterization for 

the rationale behind choosing this division point.) and 

0 otherwise. Thus, the coefficient of this variable estimates the mean annual change of the cumulative exposure 

GROUP II participants minus the mean annual change of the 

cumulative exposure GROUP I participants (See the Environmental Characterization Section for GROUP I and GROUP II 

definitions) after controlling for the other variables. 

In this regression TDI exposure is represented by 2 dummy 

variables: 

(1) Cumulative exposure category IIA which is 1 if 

cumulative exposure is greater than .0682 ppm"illonths 

and O otherwise, and 

(2) Cumulative exposure category IIB which is 1 if 

cumulative exposure is greater than .1 ppm-months 

and O otherwise. 

13 
Regression 4 

Regression 5 

Regression 6 

Thus, the coefficient of cumulative exposure category 

IIA estimates the difference in mean annual change between 

GROUP IIA and GROUP I (GROUP IIA-GROUP I). The coefficient 

of cumulative exposure category IIB estimates the difference 

in mean annual changes between GROUP IIB and GROUP IIA 

(GROUP IIB-GROUP IIA). Both of these estimated differences 

in means are after controlling for the other variables. 

Time above .02 ppm in months, 

A dummy variable. called peak exposure category II indicating that a participant belongs to time above ,02 ppm 

GROUP II (See the Environmental Characterization Section 

for definitions of GROUP I and II), The coefficient of 

this variable has been an interpretation analogous to that 

of the coefficient of cumulative exposure category II in 

Regression 2. 

Two dummy variables called peak exposure category IIA and 

peak exposure category IIB which indicate respectively 

membership in time above .02 ppm GROUPS II and IIB. The 

coefficients of these variables have interpretations analogous to those of cumulative exposure category IIA and cumulative exposure category IIB of Regression 3. 

Tables 8 through 13 present the results of these regressions, The 

numbers in parentheses in these tables are the regression coefficients divided 

by their standard errors and should be compared to percentiles of the normal 

distribution for tests of significance, Thus, a regression coefficient is 

significantly different from Oat the~= ,05 level if it divided by its 

standard error exceeds 1.96 in absolute value, 

Each observed annual change is the sum of the unobserved true annual 

change and an estimation error term. It is the variability of the true annual 

changes which we are trying to explain by the independent variables in the 

regression equations. The last column headed"% variability explained" in 

Tables 8 through 13 is the percent of true annual change variance explained 

by independent variables in the regression equations. Estimates of the true 

annual change standard deviation for each pulmonary :!;unction considered are 

given in Table 14. 

The estimation error term is the result of the variation in individual 

pulmonary function determinations about a participants regression on time. 

The differences between individual determinations and·the fitted regression on 

time are called residuals. The variation in these residuals depends on, among 

other things, technical measurement error, seasonal variability in pulmonary 

function, technician effects if they exist, and daily variability in pulmonary 

function not affecting physiologic state, The residual error standard deviation for each pulmonary function considered is given in Table 14. 

14 
Estimated mean annual changes and their standard errors are presented 

in Table 14. The remaining columns of Table 14 are more fully discussed in 

Appendix 2. Here we only note that for each pulmonary function approximately 

50% of the observed annual change variability in a participant studied at all 

nine visits is true annual change variability and hence is available for 

explanation by host factors and exposure to TDI. 

With the possible exceptions of FEF25_75 and FEF50 the spirometric 

mean annual changes found in this longitudinal study are not markedly different from cross-sectional studies. The FEF50 longitudinal mean annual change 

is 3.5 to 7.5 times that expected from cross-sectional results, depending on 

which prediction equations are used. 

Estimates of the mean annual changes in the study for DLCO 

(-. 716 ml/min-mmHg-year), K (-. 0947 min-mmHg-year} and TLC (. 32 ml/year) 

differ from Cotes' (_l) cross-sectional age coefficients. Mean annual 

changes for DLCO and Kare larger oy factors· of 3.6 and 2.4 respectively. 

The TLC annual change is statistically significantly positive whereas 

Cotes' cross-sectional age coefficient is 0. 

Longitudinal RV and (RV/TLC) X·lOO annual changes, although larger, 

are not markedly different from that expected from cross-sectional studies. 

B. Spirometry Results 

Two hundred and twenty-six participants had complete spirometry 

from three or more visits. Table 15 presents summary statistics on these 226 

participants and the 48 who did not have complete data for the required number 

of visits. There were no important differences oetween the two groups. 

The increased prevalence of atopy (23% vs 6. 3%) in the group with 

three or more good spirometry visits is possibly counterintuitive, i.e., long 

exposure to TDI which is implied by having large number of visits should result 

in an increased risk of being atopic. A more plausible explanation lies in the 

manner in which the skin testing was distributed over the nine visits of the 

study. Of the 48 participants with two or fewer complete spirometry visits, 

31 (94.6%) were not tested with s~ven or more of the possible 16 allergens, 

whereas only 30 (_13.3%) of the 226 with three or more complete visits had this 

characteristic. This "differential exposure to skin testing" makes it more 

difficult for the small number of visits group to be classified atopic, thus 

explaining the differential rates· of atopy in the two groups. The differential exposure to skin testing is a consequence of the skin testing protocol 

whereby such testing was spread out over the nine visits with not all of the 

allergens used at each visit. 

Three participants of the 226 lacked data on at least one of the 

explanatory variables and consequently have been deleted from the analysis. 

15 
In each of the six regressions, both FEV1 and FVC annual declines 

were significantly positively related to pack-years of smoking with each 

pack-year contributing ,6 ml/yr to FEV annual decline and .7 ml/yr to the 

FVC annual ·decline. Neither FEV1 nor PVC annual decline were significantly 

related to atopic status. Neither FEV%, FEF2~ 7 , nor FEF~~ annual decline J- 5 :JV 

were associated with pack-years of cigarette smoking, Atop1cs showed consistently smaller FEF25_75 and FEF50 annual declines than non-atopics at p-values 

ranging from .12 to .18, 

No spirometric measurement was significantly associated with cumulative exposure treated as a continuous variable, However, with the exception 

of FVC all annual declines became greater with increasing cumulative exposure. 

Using one-tailed tests of significance FEV1 (p = .034), FEV% (p = .014), 

and FEF25_75 (p = .004) estimated mean annual declines (after controlling for _

1 atopy ana pack years of smoking) were significantly greater (12 ml/yr, .20(yr) , 

and 41 ml/sec-yr respectively) in cumulative exposure GROUP II (i.e., those participants with cumulative exposure greater than .0682 ppm-months) than in 

GROUP I. At 14 pack years of cigarette smoking, the mean number of pack years 

for the group of the 223 participants used in this analysis, the estimated mean 

annual_~eclines (See Table 16) for non-atopics in GROUP I are 20 ml/year, 

.28 yr , and 84 ml/sec-yr respectively. Thus, even though there is a doserelated effect for FEV1 and FEV% annual decline, the absolute level of the mean 

annual declines in the higher exposure group are approximately the same as 

expected from cross-sectional studies, However, the GROUP I and GROUP II FEF25_75 estimated mean annual declines of 80 ml/sec-yr and 121 ml/sec-yr for non-atop1cs 

with O pack years of cigarette smoking are significantly greater than the crosssectional annual decline of 31 -ml/year reported by Knudson, et al ('_21 fQt !!)ale 

"never-smokers" over age 25. The· GROUP I estimated mean annual FEF50 decline of 

103 ml/sec-yr for non-atopics at O pack-years is also significantly greater than 

cross-sectional annual decline of 15 ml/sec-yr reported by Knudson, et al (2). 

The biological significance of the discrepancy between FEF25_

15 and FEF50 annual 

changes as computed from longitudinal data and that expectea based on crosssectional studies is not known. It could mean either that the population under 

study had abnormally large declines in these flow rates, indicating a deleterious 

effect on respiratory health, or that it is inappropriate to compare flow rate 

annual changes from these two types of studies. The magnitude of the 

differences between GROUP I and GROUP II (-41 ml/sec-yr for FEF25 75 and -29 

ml/sec-yr for FEF 0) reflecting a relationship to TDI exposure together with 

large annual declines for these pulmonary functions is suggestive of a hazardous 

local environment with TDI exposure increasing the risk. In any event, independent of the level of annual change, there is an exposure related effect for 

FEV1 , FEV%, and FEF25_75 annual decline, 

Table 16A presents descriptive statistics at th.e time of entry into 

the study for each of the two cumulative exposure categories, GROtn' I was 

older and contained more participants with respiratory symptoms than did 

GROUP II. Thus, the potential bias is toward underestimating the excess decline in GROUP II, 

16 
When GROUP II is dichotomized into GROUP IIA and GROUP I!B using a 

division point of .1 ppm-months, a larger mean decline is to be expected in 

GROUP IIB than in GROUP IIA if there is a dose-response relationship, For 

FEV1 , FEV%, and FEF25_

75 annual declines, which showed an association with 

the cumulative exposure dichotomized at .0682 ppm-months, this was not found. 

Although the declines were smaller in Group IIB than IIA, statistical significance (two-tailed p-values = .19, .68, and ,50 respectively) did not obtain. 

Estimated mean annual changes for these pulmonary function measurements are 

presented in Table 17 by exposure group for non-atopics with 14 pack years of 

smoking. Since large cumulative exposures are associated with participation 

from the beginning of the study to the later visits, the highest exposure 

group is possibly a survivor population. Such a selection could explain the 

non-significant decreases in annual declines from GROUP !IA to GROUP IIB. 

With the exception of FVC annual decline, all spirometric annual 

declines increased with increasing time above ,02 ppm treated as a continuous 

17 
variahle. Using one-tailed tests o~ signitlcance, p-values for the relationship between FEV1, FEV%, FEF25- 75 and FEF50 annual changes after controlling 

for atopic status and pack years of smoking were . 15, .027, .034, and .32 

respectively. 

Again, using one-tailed tests of significance FEV1 (p = .05), 

FEV% (p = .05), FEF25-75 (p = .023), and FEF50 (p = .038) estimated mean 

annual declines after controlling for atopy and pack years of smoking were 

significantly greater (11 ml/year, .15 (yr)-1, 32 1111/sec-yr, and 40 ml/sec-yr) 

in time above .02 ppm GROUP II (i.e., those participants with time above .02 

greater than .19 months) than in ·GROUP I. At 14 pack-years of cigarette smoking estimated mean annual declines (See Table 18) for non-atopics in GROUP I 

are 21 ml/year, .31 (yr)-1, 88 ml/sec-year, and 106 ml/sec-year respectively. 

Thus, as in the dichotomized cumulative exposure regression, FEV1 and FEV% 

annual declines are approximately the same as those expected from crosssectional results whereas FEF25_75 and FEF50 declines are greater than 

expected. 

When the time above .02 ppm GROUP II is dichotomized into GROUP IIA 

and GROUP IIB using a division point of 1 month, annual declines were smaller 

in GROUP IIB than in GROUP IIA for FEV1 and FEF50 and larger for FEV% and 

FEF25-75· In no case was the GROUP IIB decline significantly different at 

the .05 level from GROUP IIA. Estimated mean annual changes for these pulmonary function measurements are presented in Table 19 by exposure group for 

non-atopics with 14 pack years of smoking. 

Previous authors, notably Fletcher, et al (3), Berry (4),·and 

Berry, et al (5), have noted that observed annual change for FEV1 is the sum 

of two components: true annual change and estimation error. The magnitude 

of the estimation error is determined primarily by length of follow-up, the 

variability of an individual FEV1 determination about the true value, and to 

a lesser extent by the distribution of visits between end points. Fletcher 

et al (3) estimate the standard deviation of an individual FEV1 determination about its true values as 160 ml. Berry's (4) estimate, derived from 

several studies, is 120 ml. Our estimate of 133 ml is comparable to these 

two. 

We have estimated in our 5.5 year study that approximately 50% of 

the total variability (i.e., variability between observed FEV1 annual changes) 

is real variability (i.e., variability between true annual changes) and not 

due to estimation error. Berry, et al (5) and Fletcher et al (3) also estimate 

this percentage at 50% for studies 2.5 and 9 years in length, respectively. 

We expected that Berry's estimate of this percentag~ would be less than ours 

because his follow-up was shorter and that Fletcher's would be larger because 

his follow-up time was longer. This expectation is not realized because the 

three total variances differ. 

18 
Berry's total variance is larger than would be expected from the 

increase i.n estimation error caused by the comparatively short :follow-up 

period. Thus, although_ Berry~s real variance as percentage of total variance 

is the same as in this s-tudy-, his aosolute real variance is larger, This may 

be due to the cotton dust exposure of his· population producing abnormally 

large FEVl annual declines in some individuals, Similarly, Fletcher's total 

variance is smaller than would be expected from the decrease in estimation 

error caused by the comparatively long length of his follow-up period. This 

results in a smaller real variance possibly reflecting the relative homogeneity of his population with regard to FEV1 annual change. In addition, 

the statistical methodology employed by Fletcher assigns more of the total 

variance to estimation error than does our methodology. This would tend to 

decrease real variability as a percentage of true variability. 

Our conclusion is that these three studies for which length of 

follow-up and variability among true annual changes were quite different, 

nevertheless, exhibited remarkedly comparable standard deviations of a 

single FEVl determination about its true value and that the unexpected comparability of real variance as a percentage of total variance is explained 

by the differing population characteristics and statistical methodology. 

In short, the three studies produce no conflicting results. 

In a previous annual report dated March 15, 1976, and in Butcher, 

et al (6), we reported an annual increase in FEV1 of approximately 55 ml/year. 

This increase, based on the first five visits, was recognized as being abnormally high but was reported because extensive checking at the time revealed no reason to doubt its validity. 

Before proceeding with the analysis reported here, we examined FEV1 

for the 33 participants with complete spirometry at all nine visits in order 

to determine if there might have been a systematic bias at any of the visits, 

A graph of the mean FEV1's by visit for these 33 participants is presented 

in Figure 3 together with a least squares straight line fit to the means. 

This straight line gives an FEV1 annual change of -21 ml/year. There is an 

evident peak in mean FEV at the October, 1975, or 5th visit. A linear model 

as in Fletcher, et al (3Y, containing a secular bias term for each visit 

resulted in a significant (p <.001) bias term of 134 ml at visit 5.1 No other 

visit exhibited a secular bias. A straight line fit to the FEV1 means for 

the first five visits results in an annual change of +37 ml/year which together with the now known positive bias at visit 5 suggests that the FEV1 

annual increase reported earlier was due to the systematically high FEV1 1s 

at visit 5. 

We considered not using the visit 5 data in the current analysis 

but decided against that course for three reasons; 

1 Both FVC and FEF25_75 also exhibited significant biases at yisit 5, 

19. 
(1). A:t;ter extens:ive searching, we have found no explanation for the visit 5 

bias; (]} because visit 5 is approximately midway in the follow-up period, 

it has little effect on an individual participant's FEV1 slope provided the 

participant has at least one data point available on either side of visit 5; 

(3) when thpse participants with visit 5 as either their first or last usable 

visit were not used in the FEV1 analysis, the results were similar. 

C. Diffusion and Lung Volume 

One hundred and sixty-five participants had diffusing capacity 

determinations from three or more visits, and 183 participants had complete 

lung volume determinations from three or more visits. Tables 20 and 21 present summary statis·tics on those participants with and without three or more 

complete determinations for these two ~ts of pulmonary functions. No important differences between the two sub-groups of participants were revealed. 

Of the 165 participants with diffusing capacity determinations, one 

lacked data on at least one of the explanatory variables and was deleted from 

the analysis. Si:milarly, three participants have been deleted from the lung 

volume longitudinal analysis. 

In each of the six regressions RV and (RV/TLC} X 100 annual increase 

was significantly correlated with pack-years of smoking adding 1 ml/year to 

the RV annual increase and .01 (yrl-1 to the (RV)RC) X 100 annual increase. 

None of the other pulmonary functions· (bLco, K, or TLC} considered were 

related to pack-years of smoking. 

Of the five pulmonary functions considered, only DLco was significantly 

(p < .05) related to atopic status. This relationship was evident in each of 

the six regressions _with DLco in the atopics· declining approximately .4 (ml/minnunHg)-1 per year faster than non-atopics. This finding is inexplicable. 

With respect to the exposure indices, TLC was not significantly related 

to any of the six exposure indices. Kand DLco had a significant (p < .05) 

relation to exposure in all six regressions but it was paradoxical in nature, 

i.e., annual declines decrease with increasing exposure. RV and (RV/TLC X 100 

were not related to cumulative exposure as a continuous variable or when it was 

categorized into two or three groups. They both showed a significant (p < .05) 

paradoxical relationship with the time above .02 ppm variables, i.e., annual 

increases in these two pulmonary functions decreased with increasing time above 

.02 ppm. 

D. Respiratory Symptoms 

Four patterns of symptoms as determined by the questionnaire 

are examined in this analysis. 

20 
(.1) upper respiratory symptoms; drip at th.e hack oj; the nose, 

hay fever or its symptoms, sinus trouble or postnasμl drip; 

(2) lower respiratory symptoms: usual cough, phlegm, wheezing, 

attacks of shortness of breath with wheezing, or breathlessness when walking 

with other people; 

(3) bronchitis: usual cough and phlegm more than three months in 

the preceding year; 

(.4) dyspnea: Grade 2 or higher where Grade 2:::; when hurrying on 

level, Grade 3 = when walking with others, Grade 4 = stop for breath when 

walking at own pace. 

To be included in the longitudinal respiratory symptom analyses 

a participant must have had both an initial interview and a final (i.e., 

the latest of the last three visits) follow-up interview in order to determine 

respiratory symptom status for each of these visits. Two hundred and three 

of the total of 274 participants had sufficient information to determine at 

least one of the four respiratory symptom complexes considered. Table 22 

presents summary statistics on these 203 participants and the 71 without 

sufficient information. There were no important differences between the two 

groups. One participant lacked data on the explanatory variables and was 

discarded from the analyses. 

Tables 23 and 24 present for each of the four symptom complexes 

the number of participants in each of the four categories; (1) symptoms 

present at both the initial and last usable interview, (2) symptoms present 

at initial interview and absent at last usable interview, (3) symptoms absent at initial interview and present at the last usable interview, and 

(4) symptoms absent at both the initial and last usable interview. These 

numbers are broken down by cumulative exposure category using .0682 ppm 

months as the dividing point in Table 23 and by time above .02 ppm category 

using .19 months as the dividing point in Table 24. Each table further subdivides the exposure category by atopic and cigarette smoking status. 

If a higher proportion of participants in the higher exposure category acquired a symptom pattern between the initial and last usable interview 

(using those with any type of change as the denominator), this was taken as 

evidence of an exposure related effect. All four symptom patterns exhibited 

this effect using either cumulative exposure or time above .02 ppm category 

to represent exposure. However, statistical significance was not obtained. 

The lowest p-value was .13 for the relationship between bronchitis and cumulative exposure category. 

21 
For upper respiratory symptoms and dyspnea the percentage of 

participants changing symptom category, who went from asymptomatic to symptomatic significantly exceeded 50%, This together with high prevalence rates 

for upper (38%) and lower ("30%) respiratory symptoms at the initial interview 

suggests a hazardous local environment, either general or work related, or 

both. 

However, we have little hard information on conditions at the plant 

prior to TDI exposure to support this hypothesis. Moreover, note should be 

taken that the symptom complex d~fined as lower respiratory symptoms is quite 

broad in nature. It only requires a positive response to any one of the 

following questions: 

(1) Do you usually cough first thing in the morning in bad weather? 

(i) Do you usually cough at other times during the day or at 

night in bad weather? 

(3) Do you usually bring up phlegm, sputum or mucous from your 

chest first thing in the morning in bad weather? 

(4) Do you usually bring up phlegm, sputum or mucous :l;rom your 

chest at any other times during the day or night in bad w:eather1 

(.5) Does your breathing ever sound wheezy or whistling? 

(6} Do you have attacks of shortness of breath. with wheezing 

at present? 

(.7) Do you get short of; breath when walking with other people 

your own age on level ground? 

A similar remark holds for upper respiratory symptoms, Evidence 

that the high prevalence of lower respiratory symptoms is possibly due to the 

measuring instrument was found in results from other studies of this Unit, 

Lower respiratory symptom prevalences from four other studies were 41.0%, 

34.4%, 46.5% and 28.5%. The first three populations were exposed to either 

suspected or confirmed respiratory hazards; cottonseed dust, coffee dust, 

and asbestos, respectively, The 28,5%, which is comparable to the 29.5% observed in the study population of this report prior to TDI exposure, comes 

from a working population not exposed to any known respiratory hazard, 

Table 24A presents prevalences for bronchitis and dyspnea at initial 

and final interviews by smoking-cumulative exposure category, These prevalences were obtained for Table 23 hy collapsing across atopic status, . For both 

bronchitis and dyspnea, the increas·e in prevalence from initial to final interview is greater iri > .0682 ppm-months exposure category irrespective of smoking category. Hcwever, in no case did statistical significance obtain. 

22 
E. I.li!Dlunology 

IgE (I. U. /ml) and eosinophil levels (ccm -l) were determined at 

all nine visits and the first six, respectively. To control for possible 

seasonal effect on these two variables, a Fall and a Spring average were 

calculated for each participant. Average IgE levels across participants were 

higher in the Fall than in the Spring (269.0 vs 155.0, p < .001). There was 

no difference between average Fall and Spring eosinophil levels (227.0 vs 

224.0). 

Associations were sought between Fall IgE and eosinophil levels 

with atopy as defined by two or more positive skin test reactions to conunon 

allergens, pulmonary function at the time of initial visit, and longitudinal 

course of·pulmonary function. 

Fall IgE level was moderately correlated with skin test atopy 

(point biserial coefficient = .17, p = , 01} while Fall eosinophil level w.as 

not correlated with it (point biserial coefficient= .09, p = .12), 

Pulmonary function (in percent predicted) at initial interview was 

not significantly associated with IgE level dichotomized at 300, Only K 

was significantly associated (p = .01) with eosinophil level dichotomized 

at 250. Those with an eosinophil level less than 250 had mean K percent 

predicted equal to 101.9 as opposed to 94.4 for those with eosinophil levels 

greater than 250. NQ pulmonary function annual change showed a signi{icant 

relationship between either IgE dichotomized at 300 or eosinophil level 

dichotomized at 250 after controlling for the cumulative exposure greater 

than .0682 variable and pack-years of smoking, 

F. Detailed Analysis of FEV1 Slope 

(1) Results 

After performing the large number of regressions reported 

in Tables 8-13, a detailed analysis of the relationship between FEV1 slope and 

dichotomized (at .0682 ppm-months) cumulative exposure was performea, FEV1 slope was singled out for the following three reasons: 

1. There is an extensive body of knowledge on FEV1 slope e.g., (3), (4), (5), (35), (36), (37), (38), (39), (40) to which 

our results could be related. 

2. FEV1 when adjusted for body stature is a reliable 

and sensitive indicator of large airways obstruction. 

3. The 12 ml/yr difference in FEV between the two 

cumulative exposure categories (Table 16), although stattstically significant 

after controlling for atopy and pack years, is biologically small; it would 

be helpful to compare this exposure effect to that of cigarette smoking. 

23 
The ob.jectiye o~ the extended FRY1 analys~s was to est~temean 

annual :FEV1 de.cline_s for the six srn,ok~ng-exposure categories; . three cate.,. 

gories- of smoking (never, ex, and current cigarette SJ11oking} by two c~te.,. 

gories of exposure (less than or equal to .0682 ppm-months, and greater than 

.0682 ppm-months). This would allow a· c0.mparison of the smoking effect in 

the< .0682 ppm-months group with the exposure e£:f;ect in the never smokers, 

Atopy was not included in this analysis because the previous analyses had 

indicated that it was not an important influencing variable. 

Fletcher et . al (3J have observed that FEV leve3 as measured by 3 FEV1 divided by the third power of height, (i.e., Ftv/ht in units of Cl/m ) 

is associated with the annual decline prior to the study period. Consequently, 

in determining correlation between FEV1 slope and exposure, adjustment should 

be made for FEV1/ht3 to allow· for the possibility of an excess of rapid pre-study 

decliners (as measured by low FEV1/ht3) in the high exposure group which could 

otherwise.lead to a spurious correlation between FEV1 slope and exposure. In 

addition, there should also be adjustment for age since PEVifht3 and possibly 

FEV1 slope are related to age. 

3 FEV/ht was obtained for each participant hy aveJ;aging the available 

FEV l's for that participant, multiplying this average. br 100 and then dividing 

by neight cubed, height measured in -meters·. This quantity, referred to as 

FEV1 level, was initially categorized using division points of 55, 65, 75 and 

85. Average FEV1 slopes for these categories are shown below·. 

MEAN FEV1 SLOPE B".( FEV1 LEVEL CATEGOR.Y 

FEV1/ht3 n Mean 

(~l/m3) FEV1 Slope 

< 55 

55-64 

65-74 

75-84 

85+ 

21 

58 

76 

49 

19 

(~1/year) 

-47.5 

-20.1 

-22.6 

-20.3 

-26.2 

Recause of the lack of assQciation between FEV1 slope and level among 

the four highest categories, '.PEV level was- dichotomized using fl division point 

of 55 Centilitres- per meter cubea. This lack of association is in accordance 

with results· reported oy Fletcher e.t al (:3). 

24 
Before presenting the FEV1 slope analyses, WP. give the results of 

an analysis relating FEV1 level to age, smoking and exposure. 

Logistic regression of the dichotomized FEV1 level yielded a significant age effect (p < .01), a marginally significant ex-smoking effect as compared to never smokers (one-tailed p-value = .07) and a significant current 

smoking effect as compared to never smokers (one-tailed p-value = .03). In 

addition to these expected relationships, there was a significant association 

(p = .05) between FEV level and.exposure after controlling for age and smoking. The~e was a sma!ler proportion of participants with low FEV1 level in 

the high exposure category than in the low category. This finding appears to 

argue against a TDI exposure effect as measured by FEV level. However, as 

discussed by Fletcher et al (3), FEV1 level measures t!e effect of FEV1 slope 

prior to the study as opposed to FEV1 slope over the period of study. Thus, 

a possible explanation for the negative association between FEV1 level and 

exposure is one of selection, whereby the rapid FEV1 decliners prior to TDI 

exposure selected themselves into the low exposure category. Furthermore, 

that there is a deficiency of participants with low FEV1 level in the high 

exposure group is consistent with their younger mean age (31.7 vs 37.6 years) 

since FEV1 level has not been adjusted for age. That the high exposure group 

is younger is consistent with the fact that the jobs which lead to the high 

exposure category are entry level jobs. These necessarily go to new hirees 

who would tend to be young. 

In any event, it is important in assessing the relationship between 

FEV1 slope and exposure over the period of this study to adjust for FEV1 level 

because the known positive association between low FEV1 level and large FEV1 declines would tend to minimize the effect of exposure. 

In order ~o estimate cell means for the six smoking-exposure categories while controlling for age and FEV1 level, the regression procedure 

outlined in Appendix 2 was utilized with FEV1 slope as the independent variable and the following dependent variables: 

1. A dummy variable representing high TD! exposure - greater than 

.0682 ppm-months. 

2. Two dummy variables, one representing ex-smokers and one 

representing current smokers. 

3. The products of the two variables in 2, with the variable in 1. 

4. Age. 

5. 3 A dummy variable representing low FEV1 level (FEV1/ht less 

than 55). 

25 
The results of the regression are presented in the Table 16B by 

smoking-exposure-FEV1 level category. 

Cell means have been adjusted to the mean study population age of 

35.6 years in order to account for differing age distributions within the 

cells. The esimated cell means in the low FEV1 level category should be 

interpreted cautiously·~ especially for those cells which contain a small 

number of participants, since they are tlie result of an extrapolation. 

The coefficient of age in the multiple regression was - 5.8 millilitres per decade (one-tailed p-value = • 03) • A weak acceleration of FEV 1 loss with increasing age of approximately 5.5 millilitres per decade was also 

shown by Kauffmann et al (35) in a group of Paris area workers, Kauffman's 

age effect disappeared after adjustment for FEV1 level. In contrast, the 

age effect oos·erved in the present study occurs after controlling for FEV1 level, TDI exposure and smoking status, 

After adju~ting for age, TDI exposure, and smoking status, those with 

FEV1 level.::_ 55 Cl/-m had -mean FEV1 annual decline of 203ml/year (one-tailed 

p-value = .04) more than those witli FEV1 level> 55 Cl/m, This shows, following the arguments presented by Fletcher et al (3), that there are a group of 

people, namely those witli low FEV1 level, in this study who are lifelong rapid 

decliners. This lifelong rapid decline should not be attributed to TDI exposure. To prevent such attribution, the association between FEV1 slope and exposure has been adjusted for FEV1 level, 

Among the never smokers, after adjusting for age and FEV1 level, 

those with greater than .0682 ppm-months of TDI exposure declined on the average 38 ml/year (one-tailed p-value = .001) more than those with less exposure. 

In the ex smokers, 3/ml year difference between exposure groups was not significant. The 11 ml/year difference in the current smokers had a one-tailed p-value 

of O .1. 

Turning to the smoking effect in the.::. .0682 ppm-months participants 

there was, after adjusting for age and FEV1 level, a significant (one-tailed 

p-value = .004) difference of 27 ml per year between current smokers and never 

smokers. The 14 ml/year difference between current smokers and ex smokers was 

almost significant (one-tailed p-value = .06), The 14 ml/year difference 

between ex smokers and never smokers had a one-tailed p-value of .12. 

The 38 ml/year exposure effect in the never smokers and the 27 

ml/year current cigarette smoking effect in the low exposure group were not 

sign·ificantly different (p ... .value = , 32). 

26 
The average FEV decline, the precision of 

determination, the preciston of a participant's FEV1 of cigarette smoking observed in this study, are all 

results of other investigators. 

an individual FEV 

slope, and the effect 

consistent ~ith the 

Our average FEV1 slope of -24 ml/year (with standard error of 3.2) 

is comparable to the -30 ml/year measured by Fletcher et al (3). Ferris et 

al (36) observed a mean FEV1 annual change of -37 ml/year over six years in a 

population of males with mean age 53 years. Higgins et al (37) found an average FEV1 annual change of -34 ml/year in males aged 25 to 34 years and a -45 

ml/year average annual change in males aged 55-64 years. The follow-up period 

for this study was nine years. Petty et al (38) observed over six years a 

mean FEV annual change of -19 ml/year in a population of males, 27 per cent 

of which1had (FEV1/FVC) X 100 less than 60. Kauffmann et al (35) observed a 

-47 ml/year mean annual FEV1 annual change over 12 years in a population of 

males with mean age 41 years. Lebowitz et al (39) and Pham et al (40) were 

unable to demonstrate significant changes in FEV1 over a three year period. 

The average FEV1 decline of 24 ml/year observed n this study at 7.5 times its 

standard error Is highly significant. 

As mentioned in the Spirometry Results Section, the observed standard 

deviation of a single FEV determination of 133 ml is comparable to the 120 ml 

of Berry (4) and 160 ml ot Fletcher et al (3), Additionally, we observed a 

standard error of 25 ml/year for the slope of a participant present at all nine 

visits over the full,5.5 years of the study. This compares with the 20 ml/year 

of Fletcher et al (3) for a study of eight years and sixteen visits. 

Fletcher et al (3) found a 15 ml/year difference in FEV slope between 

current and never smokers. Kauffmann's (35) estimate of this difterence was 10 

ml per year. Results presented by Ferris et al (36) lead to an estimate of 13 

ml/year. When averaged ov~r exposure categories, we observed a 14 ml/year di~fe.J;-

ence. In the low exposure group, the difference was 27 ml/year. 

The comparability of our general results, i.e,, those not related to 

TDI exposure, with those of other investigators, demonstrates that the elev~ted 

FEV1 's at visit 5 have not produced a bias in the FEV1 slope measurements, This 

external validation provides justification beyond that given in the Spirometry 

Results section for discounting the visit 5 FEV1 measurements e;f£ect on '.eEV. 1 slope. Although we were able to detect a visit 5 bias, we have provided evia~ 

ence that it did not affect our results, This demonstrates an inherent strength_ 

of any longitudinal study of three or -more visits; in two-visit studies, it is 

impossible to detect such bias. 

27 
The 38 ml/year exposure eJ;fect in the neve~ smok.e);'s w.as not significantly different (_p.,..value = • 32) from the 27 ml/v~r smoking (current} eftect 

in the low exposure group, Thi~ comparaoility of eigarette smoking with TD! 

exposure was also found when the· smoking-exposure int;eracttons were Olllitted 

from the regression equations·, In such_ a regress:ton1 the exposure and cigar.,. 

ette smoking effects were hoth. 16 -'ID.1/year. 

At the time of entry into the study, current smokers had avera.ged 

one pack of cigarettes per day, for an average length of 18 years, ThusJ the 

data suggest that this amount of smoking produces an annual decline in FEV1 equivalent to the decline associated with TDI exposure at a concentration 0£ 

,0011 ppm for 62 months in a never smoker, The fact that th.e e,i;t'ect of TDl: 

exposure was observed in the never smokers and not in the current cigarette 

smokers suggests· that smoking may mask the effect of TDI exposure, 

28 
V, TD! REACTORS 

A. Clinical and Epidemiologic Features 

We consider those persons TDI clinically "sensitive" who 

develop recurrent respiratory signi; and symptoms upon repeated exposure to 

low concentrations of TD!, or in some cases unidentified reactants or byproducts of TDI manufacture. The definition must be qualified because some 

workers develop reversible airways obstruction in the TD! area, obtain relief 

upon transferring to other areas, but fail to react to pure TDI vapor in 

bronchoprovocation challenges. 

TDI is an irritant and is detectable in relatively low concentrations by non-sensitized persons. This probably explains why sensitization 

is most often described by the subject as a "loss of tolerance" to the 

material. Dry cough is the most frequent symptom, but chest tightness, exertional breathlessness, wheezing and shortness of breath are also common. 

Orthopnea is usually present in nocturnal attacks. Sputum is uncommonly 

reported unless it was present prior to sensitization. Reduced strength or 

stamina were common complaints of those who continued to have TD! exposure, 

and these symptoms abated following cessation of exposure. 

A delay of about one-half hour was the most commonly reported interval between known exposure and onset of symptoms. A majority of persons, 

however, reported increased symptoms after leaving the plant. suggesting 

either a dual or late reaction. Immediate onset. that is, within a few 

minutes of exposure, was rarely reported. 

Of 277 persons in the study population. 12 men (4.3%) became clinically "sensitive" to TD! (see Table 25). Nine of these 12 men became sensitized after less than 12 months of TD! exposure, eight of those after less than 

four months of exposure. Six of the 12 had known major exposure in TD! spills. 

Three of the 12 were atopic. that is, had two or more positive reactions to 

skin testing with common inhalant allergens. Six persons underwent bronchoprovocation challenge with pure TD! vapor: two of these reacted, and four did 

not react, to levels of less than .02 ppm. Five of the 12 had never smoked. 

The sensitized persons were rather evenly divided between operators in the 

TDI area and maintenance workers in the same area. The lone sensitized subject 

from outside the TDI area was a chemical engineer who may have been exposed in 

laboratory work. 

Figures 4 and 5 display the results of longitudinal lung function testing for the nine TDI clinically "sensitive" individuals with lung function testing 

after sensitization. Eight of the 12 sensitized men were tested prior to start-up 

of TD! production, and therefore prior to exposure. The others were transferred 

29 
into the TDI area or hired at different times, and were first studied at 

the succeeding visit for data collection. Three subjects (numbers 110, 

197, and 200) have shown declines in both FEV1 and FEF25_75 despite removal 

from the TDI area. Two subjects (033 and 035) have shown stable FEV1 values 

but declines in FEF25_75 . Four persons show stable to slightly increasing 

values for FEV1 after removal from TDI exposure. Two of the subjects still 

work in the TD! area and both have stable expiratory flow rates. 

Under the present conditions, however, removal from the TDI area 

cannot be considered an absolute guarantee of no further exposure. Large 

accidental TDI emissions and certain wind conditions can disperse the 

material to other parts of the chemical complex. Perceptible amounts of 

TDI can also be detected around workers with contaminated clothing and 

shoes, and this can be responsible for temporary contamination of such 

facilities as lunch rooms and the medical department. There are thus opportunities for intermittent, low-level exposures to TDI or to other materials 

from TDI synthesis, in distant areas of the chemical manufacturing complex. 

B. Immunologic Findings 

In this longitudinal study, immunologic tests were performed 

to determine whether exposure to TDI had an effect on total innnunoglobulin 

levels; whether presence of atopy was a factor in development of TDI "sensitivity"; whether total blood eosinophil levels alter following exposure to 

TDI; and whether development of humoral antibodies was a mechanism in TDI 

"sensitivity." 

The results of skin testing with common inhalant allergens showed 

that there was a similar distribution of atopic individuals among the various 

exposure groups and that this presence of atopy was not a factor in development of TDI "sensitivity" (7, 8). Total blood eosinophil counts were not 

significantly altered by exposure to TDI (8). Immunoglobulins G, A, M, 

D, and E were not significantly changed by TDI exposure (8, 9, 10). Quantitation of specific antibodies was undertaken by skin testing with a TDI-human 

serum albumin (TDI-HSA) conjugate. Results of skin testing indicated that 

TDI-HSA was a poor antigen and that anti-TDI antibodies of IgE type could not 

be detected using this material (9). Further, the radioallergosorbent test 

(RAST) was of little use with this antigen. Prausnitz-K'ustner (P-K) testing 

in monkeys was also evaluated as a method for determining development of TDI 

specific IgE antibodies. All results were negative (9). Passive cutaneous 

anaphylaxis (PCA) in guinea pigs was used to detect hererocytotropic antibodies. No positive PCA tests were obtained on serum samples from workers 

following exposure (9). 

30 
c. Provocative Inhalation Challenge with TDI 

During our prospective studies we found that approximately 

5% of workers developed clinical" sensitivity" (i.e., they complained of 

wheezing and shortness of breath when in a TDI containing area) (9). These 

subjects, where possible, were challenged with TDI (8, 10). They were 

brought to Tulane University and exposed for 15 minutes to saline vapor on 

day 1, 0.005 ppm TDI on the second day, and on subsequent days to 0.01 and 

0.02 ppm until a 20% drop in FEV was observed. Expiratory flows were derived from a forced vital capacity maneuver and determined with an electric 

dry rolling seal spirometer which provided output for volume-time and volumeflow plots of maximum forced expiration. Peak flow was also determined in a 

separate maneuver using a Wright's peak flow meter. Lung function testing 

was performed prior to exposure, and at 5, 10, 15, 30, 45, 60, 90, and 120 

minutes and thereafter at hourly intervals following challenge. The workers 

were challenged in a single blind fashion in an exposure chamber with dimensions of 2.25 X 1.89 X 2.55 meters (10.84 m3) which was under slight negative 

pressure (Figure 6) (10). The atmospheres of TDI were generated by controlled 

evaporation of TDI accomplished by passing air over the surface of TDI contained in a 250 ml gas washing bottle with effective surface area 60.8 cm2• The 

flow rate was controlled by a calibrated rotameter at between 2 to 6 liters 

per minute, depending on concentration of isocyanate vapor required. Circulation was obtained by a small fan; temperature in the room was maintained 

at 23 to 24° C and humidity was 45 to 55%. TDI quantitation was accomplished 

with a model 7000 TDI monitor. The subject was seated throughout the challenge with his breat~ing zone close to the end of the monitor to ensure accurate measurement of the concentration of TDI inhaled. Throughout the challenge, the subject was observed through a glass window in the air lock door 

by a physician. Persons reacting to TDI inhalation challenge showed three 

types of response (.6, 8, 11). A total of 28 TDI clinically "sensitive" individuals (six of whom were in the original study population) were tested by 

provocative inhalation challenge with TDI. Of these 28 persons tested, 10 

reacted to TDI _with a drop in FEV1 of greater than 20%. Six showed an inunediate 

bronchospastic response, beginning within 15 minutes after the challenge. In 

two workers, a late response was seen beginning at least one hour after the challenge and, in a further two individuals, a dual response was seen with the characteristics of both the iuunediate and late reaction. In some individuals, a 

dose response was also seen, i.e., challenge with 0.005 ppm did not elicit an 

adverse response but challenge with 0.01 ppm would elicit a bronchospastic 

reaction (Figure 7). 

D. Challenge Testing with Methacholine Chloride (Mecholyl) 

A total of 10 workers reporting "sensitivity" to TDI and 10 

non-sensitive, non-exposed workers were challenged with methacholine at the 

work plant. Seven of the ten "sensitive" individuals responded to challenge 

with a greater than 20% drop in FEV1 , whereas only one of the 10 non-sensitive 

workers reacted (12). 

31 
All subjects were tested for pulmonary function prior to commencement of challenge and demonstrated baseline flow parameters within 80% of 

predicted no.rmal values. Five breaths of physiologic phosphate buffered 

saline were inhaled through a Bird Mark 8 nebulizer and lung function was 

measured at 1,5 and 3 minutes after administration. Methacholine was administered, starting at a concentration of 5 and increasing through 10 to 25 mg/ml. 

One breath of the 5 mg/ml solution was followed by progressive increases in 

number of breaths with each of the three concentrations to a maximum of five 

breaths of the 25 mg/ml concentration. The procedure was stopped when either 

a 20% drop in FEV1 occurred or, in the absence of any airway response, when 

the maximum of five breaths of 25 mg/ml was reached. Methacholine dose 

response regression slopes were graphed for the subjects, where possible, 

with a cumulative breath unit equivalent to one breath of lmg/ml methacholine 

on the abcissa and percentage drop in FEV1 on the ordinate (11). All subjects 

who were shown to be reactive to TOI by provocative inhalation challenge also 

demonstrated high sensitivity to methacholine. 

E. Study of the Effect of Pretreatment with Disodium Cromoglycate: 

Some of the workers reacting to TOI were pretreated with 40 

mg of disodium. cromoglycate (DSCG) which was administered by spinhaler 30 

minutes before re-exposing to the concentration of TOI which had initiated the 

adverse pulmonary reaction. Workers with both immediate and dual responses 

were tested. Lung function measurements were determined as for the regular TDI 

inhalation challenge. In all three TOI reactive individuals tested, (two showing an immediate response to the challenge with TOI and the one showing a dual 

response) their adverse bronchial responses were inhibited by pretreatment with 

disodium. cromoglycate (11, 13) (Figure 8) ·• 

F. Lymphocyte Transformation and Leukocyte Histamine Release: 

Cellular studies included lymphocyte transformation following 

exposure of cells to the TOI-HSA conjugate and histamine release from leukocytes following exposure to TDI-HSA was measured. These tests were performed 

on samples collected from individuals reporting "sensitivity" to TOI. No lymphocyte stimulation was measured and no histamine released from leukocytes was 

detected (6). 

G. Lymphocyte cAMP Dose Response Studies: 

As previously reported (12, 14), we showed that TOI acts as 

a partial adrenergic agonist, however, this effect was seen with cells of 

normal individuals. We therefore examined the effect of TOI upon lymphocytes 

from TOI reactive individuals. Quantitation was performed by means of a method 

32 
developed in our laboratory (14) where lymphocytes were separated by FicollHypaque density gradient centrifugation, incubated with dilutions of isoproterenol, prostaglandin E1 or TDI, followed by washing, precipitation with trichloroacetic acid, freeze thawing, extraction with ether, and quantitation by 

radioimmunoassay. Results were interpolated from a standard graph and expressed as percent stimulation of cAMP formation. Dose response regression 

lines were determined by means of the linear ascending portion of the slopes. 

Blood samples for lymphocyte cAMP ·dose response studies of TDI reactors were 

obtained prior to, and at 15 and 120 minutes after provocative inhalation 

challenge (PIC). In lymphocytes of the two TDI reactors tested to date, dose 

response slopes following stimulation with either TDI, isoproterenol or prostaglandin E1 were markedly reduced when compared with those of normal individuals and non-TD! reactors (Figure 9). Dose response slopes did not differ from 

pre-exposure baseline levels, following challenge with TDI (11). 

H, Plasma Histamine Levels: 

Samples for venous plasma histamine determination were 

collected prior to exposure, and at 1, 5, 10, 15, and 120 minutes after 

exposure. Histamine was determined3by the enzyme isotopic method of Beaven, 

et al, with an internal control of H-histamine to measure recovery (15). 

All samples from individual patients were assayed in quadruplicate. Plasma 

histamine levels of six subjects were tested. Two were individuals with a 

strong history of TDI sensitivity who reacted to provocative inhalation challenge 

(PIC) with TDI. Two had a weak history of sensitivity and did not react to PIC. 

In no case was histamine release into venous plasma demonstrable following inhalation challenge with TDI. Baseline plasma histamine levels were all within 

normal limits (11). 

I. Determination of Serum Complement and Split Products 

of Complement 

Functional levels of total complement (CH506 were quantitated 

by standard techniques in fresh serum or serum frozen at -70 Con samples collected before exposure and 1, 5, 10, 15, and 120 minutes after TDI exposure (11). 

A hemolytic assay was also used to measure the alternative complement pathway 

proteins (APCH50). Split products and factor Bin plasma were measured by an 

iunnunoelectrophoretic assay and split products of C3 were determined by the 

counterimmunoelectrophoretic assay of Arroyave and Tan. Two TDI reactors and 

five persons demonstrated to be negative by provocative inhalation challenge 

were tested. Baseline CHSO and APCHSO levels were all within normal limits 

(60 to 120 and 15 to 45 units, respectively) for all workers and no significant 

changes in these complement levels were seen following inhalation challenge 

with TDI (11). 

33 
J. Loss of TDI and Methacholine Reactivity after 

Removal from Isocyanate ExPosure: 

One of the TDI reactive individuals, who had been studied 

intensively, has been followed longitudinally after moving to a new job 

which does not entail exposure to isocyanates. Tilis individual reacted 

originally to an exposure for 10 minutes of 0.005 ppm of TDI with an immediate bronchospastic response. He was highly sensitive to methacholine, 

showing a 38% drop in FEV1 when he received one breath of 5 mg/ml of methacholine (16). 

Six months after removal from an isocyanate containing environment, 

he was re-challenged with TDI and did not react to 15 minutes exposure to 

0.02 ppm of TDI. He was re-tested for methacholine sensitivity and it was 

found that three breaths of the 5mg/ml concentration were required to initiate a 20% reduction in FEV1 . After a further six months (i.e., one year 

following removal from TDI), he was again tested by methacholine challenge. 

At this testing, he failed to react to 5 breaths of 25mg/ml of methacholine. 

Concurrent with methacholine and TDI iphalation challenges, blood 

samples were drawn for cyclic AMP dose-response slopes following stimulation 

of his lymphocytes by prostaglandin E1 , isoproterenol and TDI. Initially, 

he was shown to have a markedly reduced dose response slope to all three 

agonists compared with normals. Six months later, there was a slight improvement in the dose response slopes. The results of the dose response 

slopes on his latest testing await completion. 

K. Concurrent Development of Food Allergy and Isocyanate Reactivity 

A further interesting aspect of this worker was that he claimed to have become highly sensitive to radishes at about the same time he became sensitive to TDI. He was challenged by permitting him to eat one small 

5 gram radish and pulmonary function testing was performed. He had an immediate severe reaction following one bite of the radish with a 75.4% decrease 

in FEV1 • He now reports that, at one year following removal from the TDI area, 

he has eaten a radish which is approximately four times as large as the one 

used in the testing with no ill effects. Interestingly, radishes contain 

ally! isothiocyanate and benzyl isothiocyanate (17). A manuscript reporting 

our findings with this worker is in preparation (18). 

L. Tolyl-specific IgE Antibodies in Serum of TDI Reactive 

Individuals: 

We assisted Dr. M. Karol of the Unive~sity of Pittsburgh by 

providing serum samples from TD! reactors to enable her to develop a new 

34 
antigen for RAST. This antigen consists of p-tolyl isocyanate conjugated 

to human serum albumin (TMI-HSA). The serum samples we supplied were from 

highly reactive individuals. Four of the five serum samples sent to Dr. Karol 

were shown to contain tolyl-specific IgE antibodies (19). Using antigen provided by Dr. Karol, we were able to confirm these results on the same serum 

samples in our laboratories. Later we prepared our own TMI-HSA antigen and 

compared this with the antigen produced by Dr. Karol. The Pearson's correlation of coefficience test was applied to the results of RAST using the same 

sera with both antigens. A value of 0.96 was obtained, indicating that our 

antigen was essentially identical to that produced by Dr. Karol. Using our 

antigen, we tested serum samples from a total of 26 individuals who had been 

shown by ourselves and another center to be reacting to provocative inhalation challenge with TDI. Depending on the method of evaluation of the results of the RAST, only 15 to 18% of the individuals were shown to have tolylspecific 'IgE antibodies (20) (Figure 10). These results show that there are 

antibodies involved in TDI asthma in a few individuals but would suggest that 

a humoral mechanism is not the definitive mechanism of TDI reactivity. 

In summary, our studies of TDI "sensitive" individuals show that 

asthmatic reactions can be elicited by brief exposure to very low concentrations of TDI. These reactions may be iimllediate, late or dual reactions 

such as those induced by avian protein, certain organic dusts or Aspergillus 

fumigatus allergens. However, our negative findings with plasma histamine 

and complement are evidence against an innnunologic mechanism. Our findings, 

that persons who react to TDI are also reactive to methacholine, confirm that 

TDI reactive individuals have irritable airways. However, our demonstration 

that not all methacholine sensitive individuals react to TDI suggests that 

reactivity to TDI is not a non-specific reaction (11). Whether methacholine 

reactivity is pre-existing or develops concurrently with development of sensitivity to TDI is not known and awaits results of prospective studies although 

the results of our longitudinal study of one sensitive worker suggest the 

latter (N). 

The demonstration of the partial agonistic activity of TDI (.12,14) 

is of great interest. TDI reactive individuals have decreased adrenergic 

agonist dose-response slopes which are associated with in vivo responses 

to TDI challenge (11). These results are in agreement with current concepts 

of asthma. Szentivanyi's theory of the mechanism of asthma proposes that 

a defective beta adrenergic response is present in asthmatic individuals 

and that this deficiency may be responsible for two effects: First, it may 

prevent production of sufficient levels of cyclic AMP in mast cells to 

protect against release of pharmological mediators such as histamine and 

slow reactive substance of anaphylaxis which are ultimately responsible for 

the bronchospastic response. Second, a deficiency in the ability to produce 

cyclic AMP can have a deleterious effect on the delicate cyclic nucleotide 

35 
balance required to maintain smooth muscle tone. Thus, our studies of TDI 

reactive individuals, to date, suggest that the most likely mechanism of 

TDI asthma is pharmacologic rather than allergic, although the latter possibility still cannot be excluded. 

Our findings that DSCG may inhibit asthmatic reactions under controlled conditions (11, 16) agree with the concept of the action of this drug 

and suggest that DSCG may be a useful prophylactic measure for workers who 

develop TDI reactivity. Expanded testing in both the laboratory and the field 

will be necessary before a definitive statement can be made however. 

Our findings in the worker who has been studied extensively following 

removal from the TDI containing area, suggest that TDI reactivity is reversible 

when the isocyanate exposure is stopped (18). The demonstration of increased 

reactivity to methacholine and diminished cAMP dose response suggests that 

TDI in some way acts to alter receptors on the cells to cause decreased cholinergic and adrenergic function. The loss of methacholine sensitivity 

suggests that this effect of TDI upon receptors may be transient and may be 

reversed, with the worker reverting to his prior health following removal from 

isocyanate exposure. Similar loss of bronchial hyperreactivity has been demonstrated following removal of reactive individuals from Western red cedar 

wood dust exposure. 

VI. CONCLUSIONS 

(1) Throughout the five-year period of this study, a comprehensive 

environmental survey ·of the plant and its workers using state of the art, 

continuous area and personal monitors demonstrated that all workers in the 

study population had some degree of TDI exposure, which depended upon job 

and location. There were frequent excursions above the current threshold 

limit value of 0.02 ppm ceiling. These exposures occurred even though the 

plant is modern and uses currently available control technology. 

(2) During annual one-month periods of concentrated maintenance 

activity in which the plant is completely overhauled, there were higher than 

usual TDI concentrations measured at the breathing zones of maintenance workers. 

(3) Although there was daily variation in TDI concentration, 

there were no systematic exposure trends demonstrated over the five-year 

period of the study. 

36 
(.4) In this five-year longitudinal study, FEV1, FEV% and FEF25_75% 

annual declines are significantly related (after controlling for smoking and 

atopic status) to TDI dose, where dose is measured by either (a) two cumulative 

exposure categories (division poin~ = .0682 ppm-months) or (b) two "time above 

O. 02 ppm" categories (division point = .19 months). 

(5) The effect of TD! exposure on FEV1 annual change appears primarily in the non-smokers and may be masked by smoking. In this population 

smoking on the average a pack of .cigarettes a day for 18 years and a TDI total 

dose in excess of .0682 ppm-months had a similar effect on FEV1 mean annual 

changes. 

(.6) FEV1 and FEV% annual declines in the high exposure categories 

were not significantly different from annual declines predicted for members 

of the general population from cross-sectional studies. FEF2s-75 and FEF50 

annual declines were significantly greater than expected in both exposure 

categories. B.oth DLco and K (diffusion constant) annual declines were significantly greater than expected, but were inexplicaoly negatively related to dose. 

The same held for RV and RV/TLC annual increases. TLC annual change showed a 

significant increase instead of expected no change. 

(7) TDI dose as estimated by cumulative exposure and peak exposure 

as measured by time spent above 0,02 ppm correlated equally well with annual 

change in lung function. 

(8) FEV1, FVC, RV and RV/TLC annual changes were significantly 

related to pack-years of cigarette smoking with associations in the expected 

direction. Only K annual decline was related to atopic status and that association was an inexplicable negative one. 

(9) Prevalences of bronchitis and dyspnea increased from preexposure baseline in the high exposure category, as measured by cumulative 

exposure, to a greater extent than ill the low- category. These differences 

in symptom increases between exposure categories were not statistically 

significant (.p-values equal to .13 and .18, respectively). 

(10) Clinically important Bronchial hypersensitivity to TDI 

developed in 4,3% of the study population, usually within a few months of 

first exposure. 

(.;1.1) Neither atopy nor smoking served to identify persons at 

higher risk of developittg TD! reactivity·. Half of the TDI reactors had been 

exposed to high levels during a spill or equipment malfunction. 

(121 Some TDI reactors have failed to attain pre-exposure or 

pre-sens.itization values of FEV1 or FEF25 ... 75%, despite transfer to other 

areas in the chemical complex. 

37 
(13). There is persuasive clinica.1 evidence for sensitizatiQn in 

some persons who £ail to react to low· concentrations (less than or equa.1 to 

0.02 ppm for 15 minutes). of pure TDI vapor . tn the exposore chamoer, 

(14) TDI 1 at certain concentra.tions, acts as a partial agonist 

upon lymphocytes to s·timulate cyclic adenosine monophosphate levels, At 

lower concentrations, it can block cyclic AMP stimulation oy isoproterenol, 

and prostaglandin E1 but not li.istam:tne, 

(15) TDI reactors are hypersensitive to methacholine C.height.-

ened bronchoconstriction as det~t'Illined by a standard inhalation multiple 

breath technique), but not all methacholine sensitive individuals are TDI 

reactive. 

(16) Lymphocytes of TDI'-sens·itive individuals have decrea.sed 

ability to respond to cyclic AMP stimulants such as the beta agonises 

isoproterenol, pros·taglandin E1 and rm:-, 

(17) Provocative inhalation challenge studies show that airways 

reactivity to TDI is reproducible in the laboratory environment and can be 

blocked by disodium cromoglycate. During bronchial reactions, no changes 

in serum complement components are observed and there is no release of 

histamine detectable in peripheral plasma. 

(18) RAST with p-tolyl isocyanate conjugated to huma.n serum 

albumin only detects tolyl specific IgE antibodies in serum o;f; 15 .... 18% of 

subjects proven by provocative inhalation challenge to be TDt reactive, 

Thus, demonstration of tolyl specific serum IgE antibody cannot he used 

to diagnose clinical sensitivity to TDI, 

(19) In addition to the ab.ave -mentioned immunologic a.nd pharma .... 

cologic activities, TDI does not appear to have an eff;ect upon; 

(a) Induct::ton of srecific antibodies in ,man as demonstrao.le 

by hemaglutination, RAST, Prausnitz-Kdstner, passive cutaneous anaphyl;uis 

or direct skin testing with TDI hl.Ill).an serum albumin conjugates, · 

(.b). Changes in levels ot serum tgG, A, M or E, 

(_c). Induction of non-specific histamine release from 

leukocytes in vitro or in vivo. 

(~) Induction of peripheral blood lymphocyte blastogenic 

transformation employing cells from "sensitive" subjects, 

38 
APPENDIX 1 

ENVIRONMENT.AL CHARACTERIZATION 

A. Introduction 

This report summarizes the environmental characterization activities in 

a new TDI manufacturing plant for a period of five years (1973-78). This 

exposure characterization survey was perhaps the most extensive and thorough 

survey undertaken of any TDI manufacturing plant in the world. Vast amounts 

of data were collected using the best and the state of the art monitoring 

techniques and methods. During the course of the study several papers were 

published (21-27), covering various aspects and findings of environmental 

characterization as related to the other parts of the study. Five annual 

progress reports containing environmental characterization sections have 

also been submitted. 

As expected in such longitudinal studies, the study goes through an 

evolutionary process. During the period of five years there were tremendous 

advancements made in the fields of personal and area monitoring, laboratory 

and field calibration of monitors, and also the recognition of the advantages 

and limitations of the measurement techniques. Also during the study, the 

Tulane industrial hygienist developed a good rapport with his counterpart in 

the plant and also with the supervisors, shift foreman and other workers of 

the plant. Better insi.ght was gained about the administrative set up and 

manufacturing operation of the plant. Appropriate refinements and changes 

in environmental characterization survey had to be made throughout the course 

of the study to adapt to these evolutionary changes. This progress report 

will delineate these evolutionary changes during the study and the necessary 

refinements made to accollllilodate these changes. 

B. Monitoring Techniques 

At the time of the writing of the proposal, the method widely used for 

analysis of TDI in air was a wet chemical method based on impinger sampling 

and colorimetry developed by Marcali (28). Until recently this was the standard recommended method for analysis of TDI. Because it is an impinger sampling method it is not ideally suited for personal sampling and the method can 

give only the integrated time weighted average. During the latter part of 1973 

a continuous paper tape monitor for area measurement of TDI became commercially 

available. This instrument is based on a paper tape method developed by Reilly 

in 1968 (29). Three of these portabie area monitors were acquired for the 

study. The TDI monitor based upon an original design by Dunlap Limited, in 

collaboration with ICI, Ltd. of U.K., continuously monitors concentrations of 

TDI in the atmosphere in the range of 0.0 to 0.08 ppm. It has a meter readout 

39 
as well as audible and visible alarms and output connections for an external 

recorder. Sensitivity and specificity to TDI is obtained by utilizing a 

continuous r.eel of chemically impregnated paper tape to sample the air. The 

tape is supplied in a cassette which will run for 168 hours or one week continuously. 

In operation, the metered volume of atmosphere is drawn through the tape 

as it moves past the exposure orifice. If TD! is present, a stain is developed 

on the tape; the intensity being proportional to the concentration of TD!. The 

exposed tape then moves past two photo detectors. One detector measures reflected light from the unexposed half and the other from the exposed half. The two 

signals are compared electronically and an output signal, proportional to the 

TD! concentration compensated for minor tape variations, is displayed in parts 

per million of TDI. The concentration is also continuously recorded on a strip 

chart recorder. A typical recorder printout is given in Figure 11. 

This was a major development in monitoring of TDI. These monitors were 

initially evaluated in the laboratory. For the evaluation the monitors needed 

to be dynamically calibrated in the laboratory. There were no simple methods 

available at the time to generate standard atmosphere of TD! for dynamic calibration. Therefore, the diffusion cell method based on the work of Allshiller 

and Cohen (30) was used to generate standard atmospheres of TD! and was subsequently used to dynamically calibrate the monitors (25). Although no exhaustive interference study was performed at this time, under ideal conditions of 

the laboratory the monitors correlated (r = .994) well with the standard Marcali method. The monitors were then evaluated in the field against the standard method by simultaneous sampling at various locations. Although the correlation (r = 0.81) in the field testing was not as good as in the laboratory 

looking at the graph _of concentration by standard method vs the monitor indicates (see Figure 12) that at higher TD! concentrations ( > .005 ppm) the 

Ma.real! method was reading consistently higher than the paper tape monitor. 

This could be explained by the positive interference in the standard method due 

to the primary aromatic amines. The primary aromatic amine (Toluene diamine) 

can be potentially present in the air because it is one of the raw materials 

used in the manufacture of TD! and it can also be formed by the hydrolysis of 

TD! itself either with moisture or by hydrochloric acid in the air. Hydrochloric acid can be in the air because it is one of the by-products in the manufacture of TD!. Although not confirmed by our llllit, it has been reported that the 

toluene diamine does.not interfere with the paper tape monitor method. Therefore, it was concluded the standard method would be overestimating the TD! concentration and cannot be used for TD! exposure characterization. Since then, 

the paper tape monitors were used exclusively for measuring exposures to TDI. 

40 
c. Area Monitoring 

Three model 7000 TDI Area Monitors (31) were used ueginning August, 

1973, until the end of 1975. The TDI Drurmning Building and several locations 

in the plant were monitored. The concentration profile for the two years 

(August 73 to July 75) in the plant and the Drumming Building is given in 

Figure 13, where the ordinate indicates the ''weekly time weighted averages" 

expressed as ppm TDI and the abcissa the dates. It is clear from Figure 13 

that there is no consistent pattern of exposure. There are a few discontinuities in the profile; they represent periods where no exposure data are 

available because of breakdown or malfunction of the TDI monitor. The levels 

of TDI both in the plant and the Drumming Building vary randomly and the 

exposures for the operators in the Drumming Building are different and independent of the exposure levels for the plant operators. 

During this period there were a number of excursions above the proposed 

threshold limit value (TLV) of 0.005 ppm TWA and also a few excursions above 

the current TLV value of 0.02 ppm. The percent excursions of weekly time 

weighted averages above both these levels is given in Table 26. Although from 

Table 26 it appears that in general the operators working in the plant have 

higher TDI exposures than those working in the Daumming Building, the table 

could be misleading for the following reasons: (1) The plant's physical 

structure is open and unprotected and direction, wind speed, humidity, temperature and precipitation. The Drumming Building is a closed system and the 

wind direction, wind speed and precipitation will have minimal effect on the 

concentration inside the building. (2) The operators in the plant are not 

stationary at one location in the plant; they move aroi.m.d considerably. In 

the Drunnning Building, the operator's movements are localized and restricted. 

(3) The plant is much more complex with multiple potential sources of emissions of TDI. To completely characterize and define the environmental levels 

of TDI, several area monitors would be needed. Even then, since the operators 

move about the plant it would be extremely difficult to monitor the exact individual exposure. The obvious alternative for quantitation of dose each worker 

receives is through personal monitoring which will be discussed in the following section. 

In order to evaluate whether the levels of TDI in the plant and the 

Dromming Building have increased or decreased an histogram or a frequency 

distribution of the weekly time weighted averages was prepared, showing the 

number of weeks for each exposure interval. The two-year period was divided 

to coincide approximately with the pulmonary function and clinical tests of the 

workers. The histograms for the plant and the Drumming Building are shown in 

Figures 14 and 15 respectively. The mean value and the standard deviation for 

each time period is shown along with the histogram. The values indicate that 

there was little improvement in TDI levels in the plant until March, 1975, and 

in the Drunnning Building there was slight increase in the exposure levels at 

that time. 

41 
The area monitoring activities were suspended for the studies 

because as is shown later on in this section, there was no correlation at 

all because the area monitor estimates of exposure to personal breathing 

zone estimates of concentration for people working in any general area 

where the area monitor is located. 

D. Personal Monitoring 

In June of 1975, continuous TDI personal monitors, based on the paper 

tape method, capable of continuously monitoring TD!, in the breathing zone 

of workers for up to eight hours, became commercially available for the first 

time. Our group acquired 12 personal monitors (Model MCM 4000) along with 

a reader/recorder (Model MCM 4100); a required accessory to get the exposure 

profile. The personal TDI monitor essentially works on the same principle 

as the area TDI monitor. The only differences are in the personal monitor 

the tape moves at a rate of 2 cm/hr compared to 10 cm/hr in the area monitor. 

However, in order to compensate for the stain intensity the sampling rate of 

personal monitor is 100 ml/min compared to 500 ml/min for the area monitor. 

The personal monitor only collects the air sample on paper tape. After the 

collection period, the stain intensity on the paper tape is read using the 

reader recorder. The concentration profile is recorded on a chart paper 

called the TDI Datagram. A typical datagram is shown in Figure 16. The 

datagram also electronically integrates the area under the curve and records 

the total dose for eight hours in ppm-hrs unit. In other words, the datagram 

provided by the personal TDI monitor, gives a total history of the TDI exposure to the worker for eight hours on a work shift. 

The TDI personal monitors were thoroughly evaluated in the laboratory before they were routinely used in the field. The flow rates were 

checked and adjusted and the battery packs were checked to see if they are 

capable of sampling at 100 ml/min for eight hours when they are fully charged 

according to manufacturer's specification. The rate of movement of the tapes 

was checked in all monitors and was confirmed to be 2.0 cm/hr. The monitors 

which could not sustain 100 ml/min flow rate or if the tape movement was 

erratic were sent back to the manufacturer. The reasons for not sustaining 

100 ml/min could either be because of a bad battery or because of breakdown 

of the pump. In either case, appropriate measures were taken to assure 

proper performance of the personal monitor. The personal monitors were also 

dynamically calibrated against the standard method. The details of calibration are given in the next section. 

Beginning in July, 1975, the workers in the TDI plant, TDI Drumming 

Building and Tank Farm, Hydrogen and Carbon Monoxi~e (HYCO) plant, Toluene 

diamine (TDA) plant, Phosgene plant, Hydrazine plant and all the maintenance 

personnel in these plants were monitored almost continuously till the middle 

of 1978 (three years). Programming schedules were drawn up for six month 

42 
periods in advance. The plant manager, superintendent, safety director 

and all senior supervisors and shift foremen were given a copy of the schedule. A typical schedule is given in Table 27. The personal samplings were 

done based on the job title rather than the personnel. In this plant, each 

job title associated with a certain plant uniquely defined a certain job 

function. All the job titles in the TD! plant, TD! Drumming, HYCO, Phosgene, TDA plants were monitored. All the job titles were monitored during 

all the three shifts (8-4, 4-12, and 12-8), except the maintenance, drumming personnel and the control population. The maintenance and drumming 

personnel work only during the day shift and so were monitored only in day 

shifts. The control population were also personally monitored only in the 

day shift. 

'Before embarking on a comprehensive personal monitoring survey, a 

study was made to determine how well the area monitoring data in the plant 

and Drumming Building and personal monitoring of job titles who should be 

working in the respective areas compared. In other words, whether the TD! 

levels measured by area monitors truly reflected the personnel exposures. 

Table 28 summarizes the results of this study. It clearly shows that the 

area monitors cannot be reliably used for measuring worker exposure. Even 

those 8-hour-TWA where the correlation was good between area and personal 

monitors inspection of the respective concentration profiles revealed that 

the integrated TWA correlation was only coincidental. The individual peaks 

and excursions were not similar in the datagram and the area monitor strip 

chart. This study ~einforced the need for extensive personal monitoring 

for exposure characterization. 

E. Quality Assurance Programs for Monitoring 

(1) General Precautions: 

Recognizing the importance of quality control in data collection for such long range prospective studies appropriate measures were 

taken early in the study. Quality control checks and measures were made 

in every step of data collection. The technician responsible for checking 

and issuing the area and personal monitor was given a written protocol of 

the procedures. He was properly instructed and trained to use the monitoring instrument in terms of calibration, testing of optics, flow rate, zero 

adjustments, changing of tapes, testing tape movement, etc. The technician 

maintained a log book, where he entered date, monitor number, calibration, 

flow rate adjustments and any other relevant adjustments he makes to the 

personal monitors before it is issued to the workers. He notes the time, 

date, the monitor number and the name of the person it was issued to for 

that day. During the shift the monitors were randomly checked to see if 

they are properly worn. At the end of the shift, the flow rates are checked 

43 
again and noted. Within 24 hours after collection, the paper tapes are 

read in the reader recorder. During that time, the paper tapes are stored 

in the dark. As soon as the paper tape is read, the name, job title, the 

date, shift,time of monitoring and the location of work is entered on the 

datagram in the field. The datagrams were then checked oy the industrial 

hygienist at Tulane and then were read and coded for storage in computer. 

The analysis of the personal monitoring and other data is described elsewhere in the report. All the personal monitors were sent back to the manufacturer for service maintenance and quality control after about 18 months 

use. 

(2) Calibration 

The area and personal monitors were routinely calibrated 

according to the manufacturer's specification. In the case of area TDI 

monitor the calibration is checked every day with the "calibration strip" 

provided with the instrument and the flow meter is checked and necessary 

adjustments made if necessary. In the case of personal monitors, the 

battery packs were charged for 14 hours at the end of every eight hour 

use. The flow rate of the personal monitors were checked using a calibrated 

rotameter before and after each use. The reader recorder is properly zeroed 

and the calibration checked before using each day. 

In order to establish that the "calibration strip" provided by the 

manufacturer is accurate, the area monitor is first calibrated with the 

"calibration strip". Then it is dynamically calibrated against the Marcali 

method by generating an atmosphere of known TD! concentration. Initially, 

the standard atmosphere of TDI was generated using the diffusion cell method. 

Later on in the study a new and more convenient generating method based on 

permeation was developed (6). When both the area monitor and the Marcali 

method indicate within experimental errors the same concentration, it is 

assumed the monitor is calibrated; if not,the standard method concentration 

is assumed correct and the reasons for differences are investigated. The 

personal monitors along with the reader/recorder system were also dynamically calibrated the same way. 

(3) Interference Studies 

One of the reasons for not using the standard Marcali method 

for exposure characterization is because the primary amines such as toluene 

diamine positively interfere in the determination. The toluene diamine 

(TWA) is a potential air contaminant in the manufacture of TD! because TDA 

is one of the raw materials used. TDA can also be produced in the air by 

hydrolysis reaction of TDI with moisture or HCl in the air. Relative humidity levels in the plant range between 70-80% through the year. Hydrochloric 

acid also can potentially be present in the air because for every mole of 

44 
TDI manufactured, four moles of HCl is obtained as a by-product. HCl will 

readily hydrolyze TDI to TDA. 

In the paper tape method, TDA is not an interferent. Investigation 

in our laboratory has shown that chlorine and nitrogen dioxide react with 

the paper to produce a diffuse brown stain. This brown stain is distinctly 

different from the characteristic bluish-purple stain produced by TDI. The 

technician handling the paper tape for the personal monitor was specifically 

instructed to check the tapes usually for unusual stains and void them if 

there were any on the tapes. Also a preliminary survey of chlorine concentrations in the air was made using Matheson-Kitagawa chlorine detector 

tubes. Generally, the chlorine levels at different locations in the plant 

w~re less than the detection limit of 0.3 ppm at which level the interference in the monitor is not significant. Figure 17 shows the extent of interference of chlorine and nitrogen dioxide with the paper tape monitor. 

(4) Evaluation of Response of Reader/Recorder for Personal 

Monitor Tape 

The miniature continuous paper tape personal monitors (Model 

MCM-4000) and the Reader/Recorder Model MCM-4100 were evaluated for .short 

term response on exposures to TDI. This kind of an evaluation was felt to 

be very important because in the real life situation the monitor is seeing 

an environment where the concentration of TDI is rapidly fluctuating and 

changing in time and space. At the end of the work shift when the tape is 

removed from the monitor and fed into the reader/recorder the recorder draws 

out a nice datagram in 30 seconds as shown in Figure 16. Until now, no one 

has investigated the degree of accuracy with respect to time, resolution 

and a combination of time-concentration exposure patterns. The personal 

monitor has been dynamically calibrated at known concentrations for long 

periods of time and it has been proved that it reads accurately. This kind 

of testing does not tell anything about short-term responses, resolution of 

peaks, or effects on peak broadening, etc. This kind of analysis was important for the study because in one of the analyses of the exposure data we were 

interested in the amount of time an operator spends above levels of ,005, 

.01, .02, .04, .06, and .08 ppm. The study has revealed a significant 

limitation of the personal monitoring system. Figure 18 will be used to 

explain this limitation. As an example, if a worker wearing the monitor 

were to be exposed as follows (see Figure 8), 0-10 mins at O ppm exposure; 

10 to 30 mins at .02 ppm exposure, 30 to 40 min at O ppm exposure, and 40 

to 50 min again at .02 ppm. Figure 18 shows approximately the shape of peaks 

obtained compared to what theoretically should be obtained. The worker has 

been exposed to 30 mins at .02 ppm. Thus, the times measured will be under-

. estimated at lower concentrations. These kind of errors is both time and 

concentration dependent. Thus, every time the concentration changes up or 

down because of this response and resolution effect the time estimated would 

be erroneous, These kinds of rapid changes in concentration and time exposed 

45 
is a very feasible situation in the TDI plant. We also noted that in spite 

of the peak broadening and shortening effect, the total dose which is the 

area under all the peaks is correct. Therefore, the calculation of the time 

weighted average concentration is correct. 

The reasons for these response effects are: 

(a) Because the paper tape in the personal monitor moves at a 

speed of 2 cm/hr, the whole'history of exposure for 8 hours is recorded in 

16 cm length of the tape. 

(b) The tape runs through the reader/recorder at a speed of a 

1 cm/second. In other words, the eight hours of exposure history is read 

in 16 seconds. 

(c) The recorder pen does not respond with the same speed. 

Therefore, the time estimate errors are amplified at higher concentrations 

and lower times of exposure. At concentration less than .01 ppm, the errors 

do not seem to be very significant. 

(d) Because the photometer scans the stain throughout its length, 

the peak broadening compensates for peak height and the total effective 

area under the curve is measured accurately. Therefore, the total dose 

and time weighted average measurements are accurate. 

In spite of these limitations considering the accuracy of TWA 

measurements, the capability of indicating the exposure profiles ~nd the 

versatility and simplicity of the paper tape monitors we feel the paper 

tape personal monitors are the best method currently available for environmental characterization of TDI for long-term epidemiologic studies. 

(5) Effect of Temperature on Measurements of TDI with 

Continuous Reading Monitors 

There are no published reports so far about the effect of temperature on the measurement of TDI using the Model 7000 TD! monitor. The 

personal and/or area monitoring was done throughout the year and the monitors were subjected to a wide range of temperatures (0-35° C). Therefore, 

a study was conducted to evaluate the performance of these monitors at 

various temperatures. Figure 19 shows a plot of the ratio of Marcali 

method concentration to the Model 700r reading vs temperature for various 

TDI concentrations. 

The monitor seems to agree well ( < 20% error) with the Marcali 

method at o0 , goc, 110c and 230c. At 4°c, there are 3 points: one with 

46 
40% error and two with less than 30% error. Because the study was conducted outdoors during winter time, we could not repeat the study at 40c, 

Considering the variability of temperature, humidity, formation of TDI 

condensation aerosols, etc., we feel there is no significant temperature 

effect on measurement with continuous monitor. 

(6) Effect of Humidity on Measurement of TDI with 

Continuous Reading Monitors 

Standard atmospheres of TDI were generated at various 

humidities and simultaneously measured with the Model 7000 monitor and the 

Marcali method. Figure 20 shows the results of this study. The paper tape 

monitor consistently reads lower at 0% RH. Between 20 to 100% RH, the 

average errors are within 20%. Since the average relative humidity at the 

plant is between 70 to 80%, we assumed that the humidity does not have any 

significant effect on measurements of airborne TDI. 

F. Miscellaneous Studies 

Because phosgene is one of the raw materials used in the manufacture 

of TDI and it is a well known respiratory irritant, a pilot scale survey 

was made to determine the extent of exposure to the study population. Personal phosgene monitors (MCM-4000) similar to the YDI monitors were used for 

this evaluation. Table 29 summarizes the results of this survey. It is 

clear from this table that the phosgene exposures were relatively minimal 

(0.004 ppm) when compared to the NIOSH reconunended TWA of 0.1 ppm for up to 

10 hour-day work week and a ceiling of 0.2 ppm. 

47 
APPENDIX 2 

STAT!STJ:CAL CONSTDERAT!ONS 

A. Statistical Methodology -Used to Define Exposure Categories 

In the Environmental Characterization section, three exposure categories based on TDI concentration as· measured oy 8-hour time-weighted 

averages and four exposure categories based on peak TDI exposure as measured by time the instantaneous TD~ concentration was above .02, .04, .06, 

and .08 ppm were defined. This· section describes the statistical methodology used to construct these exposure cat:egories. 

The construction of the exposure categories based on TDI concentration begins with 8-hour time-weighted averages· for 1949 personal samples 

on 42 job titles. Since the frequency distrioution of the time-weighted 

averages was markedly skewed to th.e right, the time-weighted averages were 

transformed by taking logarithms- to tlie base 10. The logarithm scale was 

divided into eight categories using division points -3.60, -3.30, -3.00, 

-2.70, -2,40, -2.10, and -1.80. These points correspond to division points 

.00025, .0005, .001, .002, .004 1 .008, and .016 ppm on the original scale. 

The lowest category on the log10 scale is called category 1, the next highest category 2, etc. 

The frequency distribution ny log10 category for the 1949 personal 

samples is given in Figure 1. !tis approximately symmetrical. 

Each of the ·42 jobs is represented by its cumulative distrinution 

function: 

where pi is equal to the proportion of time-weighted averages in log10 scale 

category i or less. The distance between two joos represented by: 

7 

(pli) i .. 1 and 7 

(p2i)i = 1 

is then defined to be: 

~t r2 (pli-p2i)

2 

Then two jobs are "similar" if the distance between them is small and 

"dissimilar" if the distance between them is large. 

48 
Figures 21 and 22 contain histograms tor several jobs together 

with the distances between them. 

The distance between E-operators in drumming and the bug pond 

operators is 1.13 making them far apart. The histogram in Figure 21 

visually confirms this separatipn. On the other hand, the TDI foreman 

and the ~operators in phosgene (Figure 22) are quite similar with .097 

distance between them. Intermediate between those two extremes are 

A-operators in TDI and D-operators in phosgene (Figure 22) with .37 

distance between them, TDI foreman and bug pond operators (Figure 21) 

with distance .56 between them, and E-operators in druUDD.ing and TDI 

foreman (Figure 21) with distance .67 between them, 

Using those 21 jobs with 10 or more personal samples, a cluster 

analysis was performed utilizing the above distance function. The BMDP2M 

( 32 ) cluster analysis of cases algorithm using options SUMOFSQ and 

NO STANDARDIZE with weights equal to the number of samples in job was used 

to perform the computations. When this algorithm combined clusters, the 

cumulative distribution of the new cluster was computed as the weighted 

average of the two component cumulative distributions using weights equal 

to the number of samples in each component. 

Visual inspection, without knowledge of job titles, of the cluster 

tree produced by BMDP2M resulted in three distinct clusters of jobs forming 

the basis of three exposure categories. Each of the remaining 21 jobs was 

then assigned to the category corresponding to the cluster to which it was 

nearest. 

Histograms on the log scale and descriptive statistics in ppm for 

each of the three exposure categories are presented in Figure 2 and Table 5 

respectively. The jobs which make up each category are listed in Table 4. 

The distances between the HIGH and MODERATE categories and between the 

MODERATE and LOW categories are .56 and .41 respectively, 

In determining the peak exposure categories described on t he 

Environmental Section, all 2093 personal samples were used. A job was 

represented by four numbers 

(q2' q4, q6' q8) 

where qi equals the proportion of time above .Oi ppm for i ~ 2, 4, 6, 8. 

Distance between jobs was defined in a manner analogous to that 

in the cumulative exposure case and a similar clustering performed. Tilis 

resulted in four peak exposure categories as described in Tables 6 and 7. 

49 
B. Statistical Methodology Used .in Longitudinal Pulmonary Function 

Analysis 

A large part of our effort in acces·sing the respiratory health 

effects of exposure to TDI has been directed at relating, after controlling 

for smoking and atopic status, pulmonary function annual change to an index 

of exposure. Annual change for a particular pulmonary function parameter, 

say FEV1 , was computed for each study pia.rti.cipant with three or more usable 

determinations of FEV1 as the_slope of the least squares regression line 

using FEV1 as _dependent variable and time since initial visit as the inde: 

pendent variable. In this section, the statistical methodology.for relating 

annual changes determined in th±s way to explanatory variables is developed. 

For the ith (i = 1, 2, ••• , N} study participant, let 

denote the linear regression of :FEV1 on time, Here the tij 's (j = i.,,., ,ni) 

represent those time points for which usable FEV1 's are available for the 

th i participant, ti is the mean of the ti.j's, the error terms nij are 

assumed independent and no:rmally· distributed with mean O and variance 

2 th 

• independent of study participant, ai is the value of the i study 

participant's true regression line at ti, and Si is the slope of the true 

regression line, Then each ai and ~i are estimated respectively by the 

usual least squares estimators: 

1 ni 

ai = and L yij ni 

j=l 

ni 

L yij (tij - ti) 

j=l 

bi = 

ni 

(tij - - >2 t ti 

j=l 

50 
2 

In addition,, is estimated by 

(yij - a - b (tij - - 2 

2 N ni i i ti)) 

T = r r 

i=l j=l N 

r (ni-2) 

i=l 

with 

ni 

r (n1-2)degrees of freedom. 

j=l 

Moreover, the variance of the 

estimator bi is given by 

2 

T 

ni 

(tij 

- 2 L - t ) 

j=l i 

th which depends on the observation times for the i participant. 

the 

Now let xil' xi2, ... ,xik denote the independent variables for 

th i participant wfth xi!= 1 for all i. For example with k = 4, 

xi2 might be cumulative exposure, x13 a dummy variable representing atopic 

status, and x14 = pack=years of cigarette smoking. Then we wish to 

estimate the coefficients in the expression 

k 

r 

j-1 

+ e:.f ... 

th where a

1 is the true slope for the i participant, the e:1 are independent 

2 2 and normally distributed with mean O and variance a. Thus a is the 

variance of the time annual changes. Bi not accounted for by explanatory· 

variables x11, ••• ,xik' 

51 
Standard regression techniques using the observed slopes as dependent 

variable can not be used to esti1Ilate the y' s in (1) because the variance of 

the observed slopes is not homogeneous. In order to take this lack of homogeneity into account, we proceed as follows: 

AssUllle bi and ~i are related by 

where the oi are independent and normally distributed with mean O and 

2 ni 

variance T /f,::;l - 2 C.tij - ti) • Furthermore, assume that the e:i in (1) 

and the oi are independent. It then follows that the observed slopes bi 

satisfy 

(2) 

where the oi + e:i are independent and normally distributed with mean O and variance 

n cr2 + .2 /r.i 

j=l 

2 In this model cr = Variance (e:i) is the variance of the true slopes not 

accounted for by the xil' xi2, ... ,xik' •

2 is the residual variance about 

n 

an individual participant's regression line, and ,

2

/~=l (tij - ti) 2 is the 

variance of the estimation error associated with the observed slope bi. 

52 
Since the coefficients yj in (2) are the same as those in (1), model (2) 

which relates the observed slopes to explanatory variables can be used to 

estimate the coefficients in model (1) which relates true slopes to the 

explanatory variables. Because the variances of the Ei + oi in (2) are 

heterogeneous, unweighted multiple regression techniques should not be used 

to estimate they. 'sin (2). Since consistent estimators of 

J 

n - 2 

0

2 + T2/J!i (tij - ti) , as required by weighted regression procedures are 

2 not available, the Yj's and cr have been estimated by maximizing the 

2 likelihood of bi's with respect to the Yj's and cr at the observed value of 

"?. 

T 

N 

J=l 

= 

n 

E 

j=l 

N 

E (ni - 2) 

i =1 

ni 

Specifically, letting Ki= E 

j•l 

- 2 (tij - ti) , the log likelihood of 

- N - tn 2 2 

N 

E 

i=l 

1 

2 tn 

k 

2 2 N 

(cr + T /K1

) - E 

i=l 

(b - E y 

i j=l j 

"2 whicl. yield likelihood equations at the observed value of T: 

53 
k 

(b - E yj xij) XH = 0 

N i j=l 

( = 1, 2, •.. ,k), 

E 

i=l 

( 2 + "2 /v: ) CJ • T ·~i 

k 2 

N (b - E y xij) i j=l j E 

i=l 

(c/ + ? /Ki) 2 

A solution to these equations was obtained using the International Mathematical 

and Statistical Libraries' subroutine ZSYSTM which solves systems of non-linear 

equations. 

Starting values for this iterative procedure were obtained in the 

following manner: 

1. 2 Letting bi= 9 + Ei + oi with the variance of £i equal to cr

0 

and 

N 

E Kibi b = i=l 

N 

E Ki 

i=l 

it follows (See Section 16.5 of (34) for an analogous computation) that the 

expected value of 

N 

1 E 

N-1 i=l 

54 

is "2 T + Wo 

N-1 

2 

cr 

0 
N 

N L 

where W = r K - i=l 

0 i=l i _N __ _ 

r Ki 

i=l 

N 

(b .-b) 2 

" r Ki - cr2 l. 

= i-1 

0 w 

0 

2 

as an estimate of cr • 

0 

This results in 

2 (N-1) T 

"2 r cr 

' 0 

2. · Regress bi on the xil'xi2 , ••• ,xik using weights equal to 

+~)-land take as starting values for the iterative equation solving 

K. 

l. 

"2 procedure, cr

0 

and the coefficients y01 , y 02 , .•• , Yak obtained from this 

weighted regression. 

The variance-covariance matrix of the estimators was estimated by 

the inverse of the negative of the information matrix evaluated at the 

solution of the likelihood equations. Inference on the estimated regression 

coefficients was based on the asymptotic normality of maximum likelihood 

estimators. 

As examples of above procedure, consider the following two cases 

usi~g FEV1 annual.change: 

55 
(1) k=l and xil = 1 for all i. 

(2) k = 4 and xil = 1 for all i. 

f: if cumulative < 

exposure .... .0682 ppm-months 

xi2 = 

otherwise 

[: th if i participant is non-atopic 

xi3 = 

otherwise , and 

xi4 = pack-years of cigarette smoking. 

In this situation N = 223, 

1'12 2 

T = .017572 t with 928 degrees of freedom, 

= -.0240!, 

N 

~ Ki (bi= b) 2 = 6.2107, and 

i=l 

a

2 = .000791 t

2

• 

0 

2 Then for example (1) using -.0240 t for y

01 and .000791 t for. 

56 
... "2 

a

0 , we obtain: Y1 = -.02441 with standard error= .00316 and 

"2 2 

a = .000652 1. In this case, y

1 = -.0244 is the maximum likelihood estimate 

of mean FEV1 annual change and a · = ,02551 is the maximum likelihood estimate 

of betwPen true slopes standard deviation, 

The quantity .000652 + .017572 

- 2 I:(tj-t) 

is the estimated variance of an observed slope calculated from time points 

t

1 , t 2 , .•. ,tn and .000652/(.000652 + .017572) is the proportion 

E(t --t) 2 

j 

of this variance due to "between true slopes". This is the variability we 

are attempting to explain by exposure to TDI, atopic status, and pack years 

of smoking. For a participant with FEV1 readings at all nine visits 

- 2 I:(tj-t) = 26.45 so that 49.5 per cent of variability in such a participant's 

annual change is available for explanation by the explanatory variables. 

For example (2) startings values -.0118, -.0123, .0010, -.00059, 

and .000791 were obtained for the intercept, coefficient of exposure 

categorization, coefficient of atopic status, coefficient of pack-years, 

57 
2 and o respectively. Five iterations were required to satisfy the ZSYSTM 

stopping criteria with EPS = 10-6 and NSIG = 9 (See IMSL ZSYS'IM documentation 

for definitions of EPS and NSIG.) The resulting regression equation is: 

FEV1 annual change= 

-.0120 - .0118 EXP+ .0010 ATOPY - .00058 PACK-YEARS 

(.0056) (.0064) (.0071) (.00022) where 

t if cumulative exposure > • 0682 ppm-months 

EXP = 

otherwise 

l if participant is positive on two or more skin tests 

ATOPY = otherwise 

and the numbers in parentheses are the standard errors of the regression 

coefficient. 2 The maximum likelihood estimate of o (the between true slope 

variability after removing variability explained by exposure category, atopic 

2 status, and pack years of smoking) is .000591 t. Thus using the results of 

previous example, 9. 4 percent of th.e true slope variability is explained by 

these three variables. 

58 
APPENDIX 3 

Interview Forms, Symptom Criteria, and Editorial Programs 

59 
Tul-LSU Sch. Med. 

Pul. Dis. -Iminuno. 

OCCUPATION \L STUDY VIII 

Inte •·view 

Schedule B 

DATA COLUMN 

IDENTIFICATION 

1. Study number ___ _ 

2. Social security number __ _ 

3. Name 

4. Permanent address 

Street 

Olin 

.City and State---------------

Zip Code ____ _ 

5. Schedule Code O 8 

6. Participation Number 1 

7. Code Card O 1 

8. Permanent Telephone Number ______ _ 

9. Date of Birth 

10. Age 

11. Race: White .!_ Negro~ Other l 

12. Sex: Male 1 Female 2 

13. Civil Status: Single.!_ Married~ 

Divorced 3 'Widower 4 

Separated~ Other~ 

If "other" specify: ------------

14. Name of Employing Agency-----------

15. Plant within Agency--------------

16. Date of Interview 

l 7. Name of Interviewer --------------

18. CODE CARD O 2 

60 

ready to he keypuncherl 

CODE CgJ,\J,M!\1 

1-4 

5-13 

14-3 6 

37 -55 

56-70 

71-75 

76-77 

78 

79-80 

l -4 

5-11 

17-22 

23-24 

25 

26 

27 

28-29 

30-31 

32-37 

38 

79-80 0 2 
Tul-LSU Sch. Med. 

Pul. Dis. -Immuno. 

OCCUPATIONAL STUDY VIII 

Inter,iew 

Olin 

Schedule B 

Page 2 

Data Column Code Column 

COUGH 1-4 

1. Do you usually cough first thing in the morning in bad weather? 

Yes 1 No 2 5 

2, Do you usually cough at other times during the day or at night 

in bad weather? Yes 1 No 2 6 

If "ye s" to 1 or 2 

3. Do you cough on most days for as much as 3 months of 

the year? Yes_!_ No~ N. A. 9 

4. For how many years have you had this cough? 

Less than 2 years I 

2 to 5 years 2 

5 years or more 3 

N.A. 9 

SPUTUM 

1. Do you usually bring up phlegm, sputum or mucous from your 

chest first thing in the morning in bad weather? 

7 

8 

Yes 1 No 2 9 

2. Do you usually bring up phlegm, sputum or mucous from your 

chest at any other times during the day or night in bad we.ather? 

Yes 1 No 2 10 

If "x:e s" to 1 or 2 

3. Do you bring up phlegm, sputum or mucous from your 

chest on most days for as much as 3 months of the year? 

Yes.!_ No~ N. A • .2_ 11 

4. For how many years have you raised phlegm, sputum or 

mucous from your chest? 

WHEEZING 

Less than 2 years 

2 to 5 years 

5 years or more 

N.A. 

1. Does your breathing ever sound wheezy or whistling? 

Yes 1 No 2 

2. Have you ever had attacks of shortness of breath with 

wheezing? Yes 1 No 2 

If "yes" to 1 

2 

3 

9 

3. For how many years 

of whistling? 

has your breathing sounded wheezy 

N.A. 9 9 

If "yes" to 2 

4. Do you have 

at present? 

attacks of shortness of breath with wheezing 

Yes 1 No 2 N. A. 9 

61 

12 

13 

14 

15-16 

17 
Tul-.LSU Sch. Med. 

Pul. Dis. -I.mmuno. 

OCCUPATION/-. L STUDY VIII 

Inter riew 

Olin 

Schedule B 

Page 3 

Data Column Code Column 

BREATHLESSNESS 

1. Are you troubled by shortness of breath when hurrying on level 

ground or walking up a slight hill? Yes.!_ No~ 18 

2. Do you get short of breath when walking with other people your 

own age on level ground? Yes 1 No 2 19 

If "yes" to 1 or 2 

3. For how many years have you had shortness of breath? 

N. A. 9 9 20-21 

CHEST ILLNESS 

1. During the past 3 years, how much trouble have you had with 

illnesses such as chest colds, bronchitis or pneumonia? 

0 2 3 4 5 

'------+---_.... __ ____,_ ___ .,__ _ _ ! none great deal 

2. During the past 3 years, how often were you unable to do your 

usual activities because of illnesses such as chest colds, 

bronchitis or pneumonia? One time 

2-5 times 2 

more than 5 times 3 

3. Do you think you have ever had any of these chest disorders: 

asthma, any kind of bronchial trouble, or emphysema? 

Yes 1 No 2 D. K. 3 

4. Has a doctor ever told you that you had asthma, some kind of 

bronchial trouble, or emphysema? Yes 1 No 2 

If "yes" to 4 

5. Which type? N.A. 9 

6. Have you ever had repeated attacks of pneumonia? 

7. 

8. 

Yes 1 No 2 

Have you ever been hospitalized for 

Pleurisy Yes 1 No 2 

Tuberculosis Yes 1 No 2 

Have you ever had a chest injury or chest operation? 

Yes 1 No 2 

If "yes" when? 

NASAL CATARRH 

1. Do you usually have a drip at the back of your nose? 

3. 

If "yes" to 1 

2. Do you have a drip at the 

as three months? 

Have you ever had hay fever? 

Yes 1 No 2 

back of your -nose for as much 

Yes 1 No 2 N.A. 9 

Yes 1 No 2 -

62 

22 

23 

24 

25 

26 

27 

28 

29 

30 

31 

32 

33 
Tul-LSU Sch. Med. 

Pul. Dis. -Immuno. 

OCCUPATION/IL STUDY VIII 

Inte1 view 

Olin 

Schedule B 

Page 4 

Data Column Code Column 

NASAL CATARRH (cont'd) 

4. Have you ever had a runny, stuffy or itchy nose and/ or 

sneezing for several days at a time occuring at certain times 

5. 

of the year? Yes I No 2 

Have you ever had sinus trouble or a postnasal drip? 

Yes 1 No 2 

lf "yes" to l, 3, 4 or 5 

6. Do you have any such illness a.t present? 

Yes 1 No 2 N. A. 9 

34 

35 

36 

ADDITIONAL ALLERGY HISTORY 

1. Have you ever had atopic dermatitis, by which I mean a scaling 

rash that occurs in elbow creases, behind the knees and/or 

sometimes behind the ears? Yes 1 No 2 37 

2. Have you ever had urticaria, by which I mean swollen red spots 

on the skin which may or may not be itchy? 

Yes 1 No 2 38 

lf "yes" to l or 2 

3. Do you have either such illness at present? 

Yes l No 2 N. A. 9 39 

4. Have you had more than 2 head colds each year for some time? 

Yes 1 No 2 40 

If "yes" to 4 

5. When you have a head cold, do you have runny, stuffy or 

itchy nose and/or sneezing for several days at a time? 

Yes1No2N.A.9 - -- - 6. Do any members of your immediate family (mother, father, 

brothers, sisters) have any of the allergies I have mentioned: 

a) asthma (attacks of shortness of breath with wheezing); b) 

hay fever; sinus trouble; post nasal drip; a runny, stuffy or 

itchy nose and/or sneezing for several days at a time occurring 

at certain times of the year; c) atopic dermatitis or d) 

41 

urticaria? Yes 1 No 2 42 

If "yes" to 6 

7. Which family member and what type allergy? 

Mother 1 45 

Allergy: a 1 b 2 c 3 d 4 46 

Father 2 50 

Allergy: a 1 b 2 c 3 d 4 51 

Sister 3 55 

Allergy: a 1 b 2 c 3 d 4 56 

Brother 4 60 

Allergy: a 1 b 2 c 3 d 4 61 

63 
Tul-LSU Sch. Med. 

Pul. Dis. -Irnmuno. 

PRIOR EXPOS URE 

OCCUPATION.AL STUDY VIII 

Inter·,iew 

Olin 

Data Column 

1. Have you ever worked with urathane foam, either rigid or 

flexible? Yes l No 2 

If "yes" to l 

2. Did you work in manufacturing? 

Yes 1 No 2 N.A. 9 

3. Do you or have you ever owned a fiberglass boat? 

Yes 1 No 2 

If "yes" to 3 

4, Do you or did you do your own repairs? 

Yes 1 No 2 N.A. 9 

If "yes" to 4 

5, Did you use any bouyancy materials? 

Yes 1 No 2 N.A. 2_ 

CODE CARD 0 3 

64 

Schedule B 

Page 5 

Code Column 

65 

66 

67 

68 

69 

79-80 o· 3 
Tul-LSU Sch. Med. 

Pul. Dis. -Immuno. 

OCCUPATION.AL STUDY VIII 

Inter 1 iew 

Olin 

Schedule B 

Page 6 

Data Column Code Column 

SMOKING 

1. Do you now smoke cigarettes: regularly 1 

occasionally 2 

(usually less than 1 per day) 

never 

If "regularly" now: 

2. Do you inhale? Yes 1 No 2 N. A. 9 

3. Do you smoke cigarettes: with filters 

without filters 

both with and 

without filters 

N.A. 

3 

1 

2 

3 

9 

4. How many cigarettes do you usually smoke each day at 

1-4 

5 

6 

7 

thepresenttime? N.A,11 8-9 

5. How old were you when you began to smoke cigarettes? 

N.A. 11 10-11 

6. What is the usual number you have smoked per day since 

you began to smoke? _ __, N.A. 11 12-13 

If "occasionally or "never" now: 

7. If you do not smoke cigarettes now, did you ever smoke 

them: regularly 1 

If "r~_g~larlL 

occasionally 2 

(usually less than 1 per day) 

never 

N.A. 

3 

1 

8. What was the usual number of cigarettes you smoked 

14 

per day? N.A. 11 15-16 

9. Did you inhale? Yes 1 No 2 N.A. 9 17 

10. How old were you when you began to smoke 

cigarettes? N.A. 11 18-19 

11. How old we re you when you stopped smoking 

cigarettes regularly? __ N.A. 11 20-21 

12. Were you influenced to stop smoking because you had 

a cough, wheezing or shortness of breath? 

Yes 1 No 2 N.A. 9 22 - - 13. Do you now smoke pipes or cigars: regularly I 

occasionally 2 

(usually less than 1 per day) 

never 3 23 

If "regularly" now 

14. How many pipefuls or cigars do you usually smoke each 

day? N.A. 9 9 24-25 

15. How old were you when you first smoked pipes or cigars? 

N.A,1_2 26-27 

65 
Tul-LSU Sch. Med. 

Pul. Dis. -Immuno. 

SMOKING (cont'd) 

OCCUPATIONP.L STUDY VIII 

Inter dew 

Olin 

Data Column 

16. Do you usually inhale when you smoke either pipes or 

cigars? Yes 1 No £_ N. A • .2_ 

If "occasionally" or "never" now: 

17. Ji you do not smoke cigars or pipes now, 

smoke them: regularly 

did you ever 

1 

occasionally 2 

(usually less than 1 per day) 

Ji "regularly" 

never 

N.A. 

18. How many pipefuls or cigars did you usually smoke 

3 

9 

Schedule B 

Page 7 

Code Column 

28 

2.9 

each day? N. A . .2_ 2 30-31 

19. How old were you when you first smoked pipes or cigars? 

N.A. 1.2. 32-33 

20. 

21. 

How old were you when you stopped smoking pipes or 

cigars? N.A. 99 

Did you usually inhale when you smoked either pipes 

or cigars? Yes 1 No 2 N. A. 9 

CODE CARD 0 4 

66 

34-35 

36 

79-80 0 4 

April, 1973 
0\ 

...... 

OCCUPATIONAL HISTORY 

Now I would like for you to tell me about each of the places you have worked and the types of jobs you 

have done. Please begin by telling me about your present job. Include pa-rt time jobs. Exclude jobs held 

for less than one (1) year. - - - Present Job Job No. l Job No. 2 Job No. 3 

Name and 

Addres·s of 

Company i 

I 

Kind of 

Business 

l From a 

r To s 

--

I Job I 

De scription 

- \]l 

I -I 

- ,i,.. 

,i,.. 

I I 

I I I 

I I I I 

I I I I 

'tJ 1--3 .:; .:; ........... 

I 

t:l r t;· C/l 

C: 

I C/l 

...... (l 

;::, ::;' ..., 

;::, 

c :;: ;:j (? 

0 n. 

0 

() 

() 

c::: 

'tJ 

!l> 

t-3 ,_. ,_. ::: r, 

o;z 

..... '1 !l> 

5· :i r C') :i: C/l t-3 

c::: 

t:) 

><: 

<: 

...... 

...... 

...... 

'tJ C/l "' () JQ ::r Q (1) 

0. 

cc ~ 

C') 

tJj 
Tul. -LSU Sch. Med. 

Pul. Dis. -Immuno. 

:) I 

% 

..0 

:) 

..., 

0 

z 

..0 

0 

..., 

0 

z 

..0 

:) . ..., 

0 

z 

..0 

0 

..., 

..... -0 0 >- C C ro <I) ro <I) a. Cl) Cl) 

E J-. E -0 0 ro -0 u z <i:; 

..... <I) 

0 <I) 

Cl) 

"Cl C C ..... 

<I) 

~ :l 

~ 

' 

E 

0 i... 

!i. 

OCCUPA1 IONAL STUDY VIII 

Interview 

Olin 

1-4 

5-14 

I 

a. 0 ..... 1:-< i... C ..£) u 0 0 tll ..... ..., .... Cl) 

>,vroi...<ll Q 

68 

-

Schedul<' B 

Page 9 

----

- ---------
Tul. Sch, Med. 

Pttl. Dis. - Immuno. 

OCCUPATIONAl. STUDY Vlll 

Follow-Up hterview 

Oli-1 

Schedule L> 1 

ready to he keypunched 

DATA COLUMN 

Name: ------------------------ Study Number: 

Date: 

mo. day yr. 

A. ACUTE EXPOSURE EXPERIENCE 

1. Have you had any reaction to a gas 

exposure in the last 6 months? Yes 1 No2 

If "Yes II to 1 fill out the accompanying addendum. 

"The following questions relate to your usual 

state of health in the last 6 months and do not 

include symptoms you may have had immediately 

following gas exposures. Please answer yes or no 

whenever possible.'.' 

B. COUGH (Count a cough with fir st smoke or on 

fir st going out of doors but exclude clearing 

thorat, a single or occasional cough.) 

2. Do you usually cough first thing in the 

morning in bad weather? Yes 1 No 2 

3, Do you usually cough during the day or 

night in bad weather? Yes 1 No 2 

If "Yes" to 2 or 3: 

4, Have you coughed like this on most 

days for as much as 3 months in the 

- -

last 6 months? Yes_l_ No~ N.A.-2._ 

C. PHLEGM (Count swallowed phlegm or 

phlegm more than twice a day but exclude 

phlegm from the nose.) 

5. Do you usually bring up phlegm, sputum 

or mucus from your chest first th.ing in 

the morning in bad weather? Yes 1 No 2 

6. Do you usually bring up phlegm, sputum, 

or mucus from your chest during the day 

or night in bad weather? Yes l No 2 

If "Yes II to 5 or 6: 

7. Have you brought up phlegm like this 

on most days for as much as 3 months 

in the last 6 months? Yes 1 No_£ N.A.-2._ 

69 

CODE COLUM 

1 

5 

12 

13 

14 

15 

16 

17 

18 
Tul. Sch. Med. 

Pb.I. Dis. - Immune. 

0CCUPATI0NA 1., STUDY Vlll 

Follow-Up Interview 

Olin 

DATA COLUMN 

D. CHEST ILLNESS (Count illness relating to lungs, 

including flu, but exclude heart 

trouble or external injury.) 

8. In the last 6 months have you had any chest 

illness which has kept you at hon.e for a week 

or more? 

If "Yes II to 8: 

Yes 1 No 2 

Schedule b2 

CODE COLUMJ\. 

19 

9. How many such illnesses have you had? N.A.-2...__j 21 

10. Did you bring up more phlegm than usual 

in this illness (or these illnesses)? Yes l No 2 N. A. 9 

E. CHEST TIGHTNESS 

11. Has your chest been tight or your breathing 

difficult in the last 6 months? Yes 1 No 2 

F. BREATHLESSNESS 

If unable to walk because of any condition other 

than heart or lung disease put "X" in this box and go 

to question 16. n 

12. Are you troubled by shortness of breath when 

hurrying on the level or walking up a slight 

hill? Yes 1 No 2 N.A. _j_ 

If"Yes"tol2: 

13. Do you get short of breath walking with 

other people at an ordinary pace on the 

level? Yes 1 No 2 N.A.-2..._ 

If 11Yes 11 to 13: 

14. Do you have to stop for breath walking 

at your own pace on the level? Yes 1 No 2 N.A. _j_ 

If 11 Yes 11 to 14: 

15. Are you short of breath on washing 

or dr e s sing ? Yes 1 No 2 N.A. _j_ 

G. WHEEZING 

16. Has your breathing been wheezy or whistling 

in the last 6 months? Yes_l_ No..l_ 

1 7. Have you had attacks of shortness of breath 

with wheezing? Yes_l_ No___I 

If 11Yes" to 17: 

18. Do you have attacks of shortness of breath 

with wheezing at present? Yes 1 No 2 N.A._j_ 

70 

23 

24 

25 

26 

27 

28 

29 

31 

32 
Tul. Sch. Med. 

Pul. Dis. - Immuno, 

H. NASAL CATARRH 

OCCUPATIONAL STUDY VIII 

Follow-Up Interview 

Oli 11 

DATA COLUMN 

19, Do you usually have a drip at the back of 

your nose? Yes 1 No 2 

If "Yes" to 19: 

20. Have you had a drip at the back of your 

nose for as much as 3 of the last 6 

months? Yes 1 No 2 N. A._1__ 

I. 

21. Do you have a runny, stuffy, or itchy nose, 

or sneezing for several days at a time 

occurring at certain times of the year? Yes 1 No 2 

22. Do you have sinus trouble or a postnasal 

drip? Yes 1 No 2 

ALLERGY 

23. Have you had asthma in the last 6 months? Yes 1 No 2 

24. How many head colds have you had in the 

last 6 months? -- -- If other than "none' 1: 

25. How many weeks did they last, all 

together? -- -- 26, When you have a head cold do you have a 

runny, stuffy or itchy nose, or sneezing 

fpr several days at a time? Yes 1 No 2 

27, Do you take me di cation for allergies? Yes 1 No 2· 

If "Yes 11 : 

2 8. What medication? ------------------ 2 9, How frequently? __________________ _ 

J, OTHER ILLNESSES 

30, Since we last saw you, has a doctor told 

you that you had . 

a. a heart condition? 

b. T. B.? 

c. emphysema? 

d. chronic bronchitis? 

e. pneumonia? 

If "Yes" to pneumonia: How many times? 

31. Have you had any operations or injuries 

affecting your chest or been told something 

was wrong with your chest x-ray since we 

Yes 1 No 2 

Yes 1 No 2 

Yes 1 No 2 

Yes 1 No 2 

Yes 1 No 2 

-- --

last saw you? Yes 1 No 2 

N.A. -1..-1.. 

N. A._1_ J.... 

Schedule b3 

CODE COLU:tvl; 

33 

34 

35 

36 

37 

38 - --

41 --

43 

44 

45 

46 

47 

48 

49 

51 --

53 

If "Yes 11 to 31: Please describe: ____________________ , 

==========================---======~=c~ ... ..... . 71 
Tul. Sch. Med. 

P11l. Dis. -Immuno. 

OCCUPATIONPL STUDY vrn 

Follow-Up Interview 

Schedule b4 

Oliri 

DATA COLUMN CODE COLUM 

K. SMOKING HISTORY 

32. Do you smoke regularly? Yes 1 No 2 54 

If 11Yes 11 to 32: 

33 •..• cigarettes? Yes_l_ No 2 N.A . ....2.._ 55 

If 11Y es 11 to 3 3 : 

34. How many packs do you smoke each 

day? __packs= __ Cig. N.A. 9 9 56 

3 5 • Do you inhale ? 

36. Do you smoke pipes regularly? 

If 11Yes'' to 36: 

37. How many pipesful do you smoke each 

day? 

3 8. Do you inhale ? 

39. Do you smoke cigars regularly? 

If 11Yes 11 to 39: 

40. How many cigars do you smoke each 

day? 

Yes 1 No 2 N. A. 9 

Yes....1. No_l__ N.A . ....2.._ 

- _ N.A . .....2..._--2._ 

Yes 1 No 2 N.A. -2... 

Yes 1 No 2 N.A. 9 

- - N. A • --2._ --2._ 

41. What type of cigar clo you smoke? _________ _ N.A. ....2.... 

42. Do you inhale ? Yes 1 No -Z N.A . ....2.... 

Schedule Code 

L. EXPOSURE INFORMATION 

43. Have you been off work for more than 3 

weeks in the last 6 months? Yes 1 No 2 

If 11Yes 11 to 43: 

44. For how many weeks?--------------------

45. What did you do in that time? ________________ _ 

46. Which zone do you work in? North 1 South 2 East 3 West 4 Central 5 

All Over 6 Other: ______ _ 8 

If specific zone is given: 

58 

59 

61 

63 

64 

65 

67 

68 

75 

1 

5 

6 

47. Which area in that zone? _______________ N.A._.2...-2._ 7 

48. What is your complete job title? 9 

0 8 ----

0 6 

Study No. 

Study Classification 12 

72 
Tul. Sch. Med. 

Pu.1. Dis. -Immuno. 

OCCUPATIONAL STUDY VIII 

Follow-Up [nterview 

Olin 

DATA COLUMN 

L. EXPOSURE INFORMATION (cont'd) 

49. How frequently do you notice being exposed 

to thE" following gases? Frequency 

a) Ammonia? 

b) TD!? 

c) Phosgene? 

d) Chlorine? 

' 

e) Residue? 

Duration 

Olin's Exposure Classification 

5 0. Inter viewer : 

S cl'ie dule b 5 

CODE COLUM i 

13 

21 

31 

41 

35 

I(, 

--------------------------- 73 

Schedule Code 75 

Rev. 11/76 

73 
1u1. , ·u •. Med. 

Pul. Dis. -Immuno. • 

Vl-'--UPA'l1u; i\LS1UJ/'i V11I 

Follow- Up Interview 

Olin 

DATA COLUMN CODE COLD . 

K. SMOKING HISTORY 

32, Do you smoke regularly? Yes 1 No 2 54 

If "Yes" to 32: 

33 ••.. cigarettes? Yes_l_ No~ N.A._2_ 55 

If "Yes" to 33: 

34. How many packs do you smoke each 

day? __packs= __ Cig. N.A . ..1_..l_ 56 

3 5. Do you inhale? 

36. Do you smoke pipes regularly? 

If "Yes" to 36: 

37. How many pipesful do you smoke each 

day? 

38. Do you inhale? 

39. Do you smoke cigars regularly? 

If "Yes II to 3 9: 

40. How many cigars do you smoke each 

day? 

Yes 1 No2 N.A . ..l_ 

Yes_l_ No~ N.A._2_ 

- _ N.A.~_9_ 

Yes 1 No 2 N.A._j_ 

Yes 1 No 2 N. A • ..1_ 

_ N.A._9__9_ 

41. What type of cigar do you Rmoke ? _________ _ N.A.~-

42. Do you inhale? Yes 1 No 2 N.A. _j_ 

Schedule Code 

58 

59 

61 

63 

64 

65 

67 

68 

75 0 8 

----~ 

0 6 

L, EXPOSURE IN FORMATION l Study No. 

46. Which zone do you work in? North_l_ South..1_ East2._ West..i_ Central2._ 

·All Over 6 Other : 8 6 -------- If specific zone is given: 

47. Which area in that zone? _______________ N.A._j__j_ 7 

48. What is your complete job title? 9 

Study Classification 

Olin's Exposure Classification 

50. Interviewer=·---------------------------

Schedule Code 

74 

12 

72 

73 

75 
SYMPTOM CLASSIFICATIONS 

Bronchitis 

Current Bronchitis 

Usual cough and phlegm for 

more than 3 months per year 

Chronic Bronchitis 

Current bronchitis for two 

or more years 

Lower Respiratory Symptoms 

Cough, phlegm, wheezing, SOB 

with wheezing, or SOB when 

walking with others of own 

age 

Upper Respiratory Symptoms 

Drip at back of nose, hay 

fever, or current sinus 

trouble 

Dyspnea 

Grade 1 

Grade 2 

Grade 3 

Grade 4 

Grade 5 

Respiratory Atopy 

Ever had asthma or hay fever 

or any trouble around grass, 

pollen, etc. 

Dermal Atopy 

Atopy 

Ever had eczema or hives, and 

a positive family history of 

asthma or hay fever 

Either dermal or respiratory 

atopy 

Smoking 

Current Cigarette 

Ex-Cigarette 

Pipe/Cigar 

Never Smoker 

Initial Interview 

1 in cc 5 or 6 and 

1 in cc 7 and 

1 in cc 9 or 10 and 

1 in cc 11 

Current bronchitis and 

2 or 3 in cc 8 and 

2 or 3 in cc 12 

1 in cc 5 or 6 or 9 

or 10 or 13or IT 

or 19 

1 in cc 32 or 36 

2 in cc 18 and 19 

1 in cc 18 and 

1 in cc 19 

2 in cc 18 and 19 

not applicable 

not applicable 

1 in cc 14 or 33 

or 34 

1 in cc 37 or 38 and 

1 in cc 42 

either of the above 

1 in cc 5 

2 or 3 in cc 5 and 

1 in cc 14 

2 or 3 in cc 5 and 

1 in cc 23 or cc 29 

2 or 3 in cc 5 and 

2 or 3 in cc 23~-

75 

Follow-Up Interview 

1 in cc 13 or 14 and 

1 in cc 15 and 

1 in cc 16 or 17 and 

1 in cc 18 

not applicable 

1 in cc 13 or 14 or 16 

or 17 or 26or 29 

or 31 

1 in cc 34 or 36 

2 in cc 25-28 

1 in cc 25 and 

2 in cc 26-28 

1 in cc 25-26 and 

2 in cc 27-28 

1 in cc'25-27 and 

2 in cc 28 

2 in cc 25-28 

not applicable 

not applicable 

not applicable 

1 in cc 54 and 55 

not applicable 

1 in cc 54 and 

1 in cc 59 or 64 

2· in cc 54 

Listing of Computer Program to Edit Initial Interview 

00010 C 

00020 

00030 

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00120 

00130 

00140 

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00300 

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00320 

00330 

00340 

00350 

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00370 

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C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

00470 C 

00480 

00490 

00500 

C 

PROGRAM TO PROCESS T.D.I. INITIAL INTERVIEWS 

(FORMERLY CALLED INITLB. FOR) 

WRITTEN BY LARRY JANESKI MARCH, 1978 

(WITH CODE SEX;MENTS FROM TDIINV. FOR) 

UPDATED BY RAY l<ERN MARCH, 1979 

IMPLICIT INTEX;ER (A-Z) 

DIMENSION CC(80), OTHER(5) 

DOUBLE PRECISION XFILE 

REAL YEARS,PACKS,YRSTOP,AGE,S1,AGE1,AGE2,PYRS 

DATA OTHER/5*0/ 

OPEN(UNIT=01,ACCESS='SE;?IN',FILE='TDINTL.INV') 

OPEN(UNIT=20,ACCESS='SE;20UT',FILE='TDEXTI,INV') 

XFILE='TDBAKI.INV' 

OPEN(UNIT=21,ACCESS='SE;?OUT',FILE=XFILE) 

800 FORMAT (A4,74X,12) 

801 FORMAT (80I1) 

900 FORMAT(/' DO YOU WANT DATA EXTRACTED(Y ORN)?'$) 

802 FORMAT (A1) 

908 FORMAT (A4,1X,3I2,6I2,2I1,5I2,5X,F5.2,2I2,4F6.2,1X,3A2) 

TYPE 900 

ACCEPT 802,IEXT1 

READ FIRST CARD FOR ID# 

3 CONTINUE 

READ(01,800,END=100)ID,CARD 

IF (CARD.EZ.01) GO TO 4 

CALL ERROR ( ID, ' CARD cxrr OF SEQUENCE 1 ) 

STOP 

READ SECOND CARD FOR DATE INFO 

4 CONTINUE 

READ (01,801) CC 

IF(CC(80).EQ.2) GO TO 5 

CALL ERROR (ID, 1 CARD cxrr OF SEQUENCE' ) 

STOP 

DATE CALCULATION 

5 CONTINUE 

MO= CC(32)*10 + CC(33) 

77 
00510 

00520 

00530 

00540 

00550 

00560 

00570 

00580 

00590 

00600 

00610 

00620 

00630 

00640 

00650 

00660 

00670 

00680 

00690 

00700 

00710 

00720 

00730 

00740 

00750 

00760 

00770 

00780 

00790 

00800 

00810 

00820 

00830 

00840 

00850 

00860 

00870 

00880 

00890 

00900 

00910 

00920 

00930 

00940 

00950 

00960 

00970 

00980 

00990 

01000 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

YR= CC(36)*10 + CC(37) 

DA= CC(34)*10 + CC(35) 

AGE CALCULATION 

AGE= CC(23)*10 + CC(24) 

VISIT CALCULATION 

VISIT = '00' 

IF(YR.EQ.73.AND.ftoD.GE.03.AND.MO.LE.05) VISIT= '01' 

IF(YR.EQ.73.AND.MO.GE.10.AND.MO.LE.12) VISIT= '02 1 

IF(YR.EQ.74.AND.M:>.GE.08.AND.MO.LE.10) VISIT= '04' 

IF(YR.EQ.75.AND.K>.GE.02.AND.MO.LE.04) VISIT= '05' 

IF(YR.EQ.75.AND.K>.GE.02.AND.MO.LE.11) VISIT= '06' 

IF (VISIT.NE. 1 00') GOTO 6 

BAD DATE 

CALL WARN (ID, 1 INTERVIEW DATE 1 ) 

SKIP RECORD 01 

SKIP RECORD O 1 

GO TO 3 

FOR EACH CLASS OF SYMPTCMS (LRS,URS,BRON.), DETEIMINE IF SYMPTOM 

WAS PRESENT/ABSENT FOR INITIAL INTERVIEWS 

LCMER RESPIRATORY SYMPTCM - INITIAL INTERVIEW 

6 CONTINUE 

READ (01,801) CC 

IF (CC(80) .EQ. 3) GO TO 7 

CALL ERROR (ID, 'CARD OUT OF SEQUENCE' ) 

STOP 

7 CONTINUE 

LRD = 0 

IF (CC(05).EQ.1.0R.CC(06).EQ.1.0R.CC(09).EQ.1.0R.CC(10).EQ.1 

*.OR.CC(13).EQ.1.0R.CC(17).EQ.1.0R.CC(19).EQ.1) 

*LRS = 1 

IF (CC(05).EQ.2.AND.CC(06).EQ.2.AND.CC(09).EQ.2.AND. 

* CC(10).EQ.2.AND.CC(13).EQ.2.AND.CC(19).EQ.2.AND. 

* (CC(17).EQ.2.0R. CC(17).EQ.9)) 

*LRS = 2 

IF (LRS.EQ.O) CALL EXCEPT (ID, 'LCMER RESP. SYMPTCM') 

UPPER RESPIRATORY SYMPTCM - INITIAL INTERVIEW 

URS= 0 

IF (CC(32).EQ.1.0R.CC(36).EQ.1) URS= 1 

IF ((CC(32).EQ.2.0R.CC(32).EQ.9).AND. 

78 
01010 

01020 

01030 

01040 

01050 

01060 

01070 

01080 

01090 

01100 

01110 

01120 

01130 

01140 

01150 

01160 

01170 

01180 

01190 

01200 

* (CC(36).EQ.2.0R.CC(36).EQ.9)) URS= 2 

IF (URS.EQ.O) CALL EXCEPT (ID,'UPPER RESP. SYMPTOM') 

C 

C BRONCHITIS - INITIAL INTERVIEW 

C 

C 

C 

COUGH=O; PHLEG=O; CCOUGH=O; CPHLEG=O 

CBRON=O: EBRON=O 

EXPANDED DEFINITION 

IF ((CC(05).EQ.1.0R.CC(06).EQ.1).AND.CC(07).EQ.1) COUGH=1 

IF ((CC(09).EQ.1.0R.CC(10).EQ.1).AND.CC(11).EQ.1) PHLEG=1 

IF ((CC(05).EQ.1.0R.CC(05).EQ.2).AND. 

* (CC(·06) .EQ.1.0R.CC(06) .EQ.2) .AND. 

* (CC(07).EQ.2.0R.CC(07).EQ.9)) COUGH= 2 

IF ((CC(09).EQ.1.0R.CC(09).EQ.2).AND. 

* (CC(10).EQ.1.0R.CC(10).EQ.2).AND. 

* (CC(11).EQ.2.0R.CC(11).EQ.9)) PHLEG = 2 

IF (COUGH.EQ.1.AND.PHLEG.EQ.1) EBRON= 1 

IF (COUGH.EQ.2.0R. PHLEG.EQ.2) EBRON= 2 

IF (EBRON.EQ.O) CALL EXCEPT (ID,'CURRENT BRONCHITIS') 

01210 C 

01220 

01230 

01240 

01250 

01260 

01270 

01280 

01290 

01300 

01310 

01320 

01330 

01340 

01350 

01360 

01370 

01380 

01390 

01400 

01410 

01420 

01430 

01440 

01450 

01460 

01470 

01480 

01490 

01500 

01510 

01520 

01530 

C CHRONIC DEFINITION 

C 

IF (COUGH.EQ.1.AND.(CC(08).EQ.2.0R.CC(08).EQ.3)) CCOUGH = 1 

IF (COUGH.EQ.1.AND.CC(08).EQ.1) CCOUGH = 2 

IF (COUGH.EQ.2.AND.CC(08).EQ.9) CCOUGH = 2 

IF (PHLEG.EQ.1.AND.(CC(12).EQ.2.0R.CC(12).EQ.3)) CPHLEG = 1 

IF (PHLEG.EQ.1.AND.CC(12).EQ.1) CPHLEG = 2 

IF (PHLEG.EQ.2.AND CC(12).EQ.9) CPHLEG = 2 

IF (CCOUGH.EQ.t.AND.CPHLEG.EQ.1) CBRON = 1 

IF (CCOUGH.EQ.2.0R. CPHLEG.EQ.2) CBRON = 2 

IF(CBRON.EQ.O) CALL EXCEPT (ID,'CHRONIC BRONCHITIS') 

C ATOPY - FROM INITIAL INTERVIEW 

C 

C 

C 

C 

C 

RATOPY=O; DATOPY=O; ATOPY=O 

IF(CC(14).EQ.1.or..CC(33).EQ.1.0R.CC(34).EQ.1) RATOPY = 1 

IF (CC(14).EQ.2.AND.CC(33).EQ.2.AND.CC(34).EQ.2) RATOPY = 2 

IF ((CC(37).EQ.1.0R.CC(38).EQ.1).AND.CC(42).EQ.1) DATOPY = 1 

IF ((CC(37).EQ.2.AND.CC(38).EQ.2).0R. 

* ((CC( 37) .EQ .1 .OR.CC(38) .EQ.1 )AND.CC(42) .EQ.2)) DATOPY = 2 

IF (RATOPY.EQ.1.0R.DATOPY.EQ.1) ATOPY = 1 

IF (RATOPY.EQ.2.AND.DATOPY.EQ.2) ATOPY = 2 

IF (ATOPY.EQ.O) CALL EXCEPT (ID.'ATOPY SYMPTOM') 

DYSPNEA (3 GRADES: 1=NO, 2-3=YES) 

DYSP = 0 

IF (CC( 18) .EQ.2.AND.CC( 19) .EQ.2) DYSP = 1 

IF (CC(18).EQ.2.AND.CC(19).EQ.1l DYSP = 1 

IF (CC(18).EQ.1.ANO.CC(19).EQ.2) DYSP = 2 

IF (CC(18).EQ.1.AND.CC(19).EQ.1) DYSP = 3 

IF (DYSP.EQ.O) CALL EXCEPT (ID, 'DYSPNEA GRADE') 

79 
01540 

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01590 

01600 

01610 

01620 

01630 

01640 

01650 

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01670 

01680 

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01700 

01710 

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01730 

01740 

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01800 

01810 

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01840 

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01870 

01880 

01890 

01900 

01910 

01920 

01930 

01940 

01950 

01960 

01970 

01980 

01990 

02000 

02010 

02020 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

02030 C 

15 

16 

SMOKING - FROM INIITAL INTERVIEW (NEXT CARD) 

CONTINUE 

RFAD (01,801) CC 

IF (CC(80) .EQ. 4) GO TO 16 

CALL ERROR (ID, 'CARD OUT OF SEQUENCE') 

STOP 

CONTINUE 

SMOKE=O; PACKS=99.99; YEARS=99.99; YRSTOP=99.99; PYRS=-1.00 

IF ((CC(05).EQ.1.AND.CC(14).EQ.9).0R. 

* (CC(14).EQ.1.AND.(CC(05).EQ.2.0R.CC(05).EQ.3))) 

*SMOKE= 1 

IF ( (CC( 05) .EQ. 2 .OR.CC( 05) .EQ. 3) .ANO. 

* (CC(14).EQ.2.0R.CC(14).EQ.3).AND. 

* (CC(23).EQ.1.0R.CC(29).EQ.1)) 

*SMOKE= 2 

IF((CC(05).EQ.2.0R.CC(05).EQ.3).~D. 

* (CC(14).EQ.2.0R.CC(14).EQ.3).AND. 

* (CC(23).EQ.2.0R.CC(23).EQ.3)) 

*SMOKE = 3 

IF(SMOKE.NE.O) GO TO 17 

CALL EXCEPT (ID,'SMOKING STATUS') 

00 TO 70 

17 CONTINUE 

DECISION FOR PACKS, YEARS, STOP YEARS 

,IF ( SMOKE. EQ. 1 ) GO TO 2 0 

YRSTOP = 99.99 

YEARS= 0.0 

PACKS= O.O 

OOTO 70 

CIGARETTE SMOKER 

20 CONTINUE 

IF (CC(06).NE.1) GO TO 35 

PERSON WHO NOW SMOKES 

YRSTOP = O.O 

S1 = CC(12)*10 + CC(13) 

CHFl:K FOR VALID PACKS 

IF (S1,GT.O.O.AND.S1.LT.77.0) GO TO 21 

S1 = CC(08)*10 + CC(09) 

IF (S1.Gl.O.O.AND.S1.LT.77.0) GO TO 21 

OOTO 25 

HERE IF VALID PACKS 

80 
02040 

02050 

02060 

02070 

02080 

02090 

02100 

02110 

02120 

02130 

C 

C 

02140 C 

02150 

02160 

02170 

02180 

02190 

02200 

02210 

02220 

02230 

02240 

02250 

02260 

02270 

02280 

02290 

02300 

02310 

02320 

02330 

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02350 

02360 

02370 

02380 

02390 

02400 

02410 

02420 

02430 

02440 

02450 

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02470 

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02490 

02500 

02510 

02520 

02530 

02540 

02550 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

21 CONTINUE 

PACKS= S1/20. 

CllECK FOR VALID AGE 

25 IF (AGE.GT.o.o.AND.AGE.LT.77.0) GOTO 27 

OOTO 70 

CllECK FOR VALID STARTING AGE 

27 CONTINUE 

AGE1 = CC(10)*10 + CC(11) 

IF (AGE1.GT.O .AND. AGE1.LT.77) GO TO 30 

00 TO 70 

HERE IF VALID AGE 

30 CONTINUE 

YEARS= AGE - AGE1 

OOTO 70 

HERE IF PAST SMOKER 

35 CONTINUE 

IF (CC(14).NE.1) GO TO 70 

S1 = CC(15)*10 + CC(16) 

IF (S1.GT.O .AND, Sl.LT.77.0) GOTO 40 

GOTO 45 

40 CONTINUE 

PACKS= S1/20. 

CllECK FOR VALID AGE 

45 IF (AGE.GT.O.O~AND.AGE.LT.77.0) GOTO 47 

GOTO 70 

CllECK FOR VALID STARTING AGE 

47 CONTINUE 

AGE1 - CC(18)*10 + CC(19) 

IF (AGE1.GT.o.o .AND. AGE1.LT.77.0) GO TO 48 

00 TO 70 

CllECK FOR VALID STOPPING AGE 

48 CONTINUE 

AGE2 = CC(20)*10 + CC(21) 

IF (AGE2.GT.O.O .AND. ~E2.LT.77.0) GO TO 50 

00 TO 70 

HERE IF AGES ARE VALID 

50 CONTINUE 

YRSTOP = AGE - AGE2 

YEARS ·= AGE2 - AGE1 

PACK*YEARS CALCULATION 

70 CONTINUE 

IF (PACKS.EQ.99.99) CALL EXCEPT (ID,'PACICS/DAY SMOKED') 

IF (YEARS.EQ.99.99) CALL EXCEPT (ID, 'YEARS SMOKED') 

IF (SMOKE.EQ.l.AND.YRSTOP.E.Q.99.99) 

81 
02560 

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02580 

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02610 

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02830 

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02880 

02890 

02900 

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02920 

02930 

02940 

02950 

02960 

02970 

02980 

02990 

03000 

03010 

03020 

03'030 

03040 

03050 

03060 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

*CALL EXCEPT (ID,'YRS STOPPED SMOKING') 

IF (PACKS.EQ.99.99.0R.YEARS.EQ.99.99) GO TO 75 

PYRS = PACKS*YEARS 

75 CONTINUE 

IF(TEXT1 .NE. 'Y') GO TO 80 

w"'RITE ON TO EXTRACT FILE 

71 CONTINUE 

STUDY=1 08 1 

PLANT= 0.0 

HAZOCC = 0 

REX:ORD = '08' 

WRITE(21,908) ID,MO,DA,YR,LRS,URS,CBRON,EBRON,DYSP,ATOPY,RATOPY, 

*DATOPY,OTHER,PLANT,HAZOCC,SMOKE,PACKS,YEARS,YRSTOP,PYRS, 

*STUDY,VISIT,RECORD 

WRITE(20.908) ID,MO,DA,YR,LRS,URS,CBRON,EBRON,DYSP,ATOPY,RATOPY, 

*DATOPY ,OTHER,PLANT,HAZOCC,SMOKE,PACKS, YEARS, YRSTOP,PYRS, 

*STUDY,VISIT,RECORD 

ID 0210 IS MISSING INITIAL INTERVIEW. SPECIAL EXTRACT FOR HIM. 

IF (ID.NE.'0209') GO TO 80 

ID='0210'; M0=9; DA=15; YR=74; LRS=O; URS=O; CBRON=O; EBRON=O 

DYSP=O; ATOPY=O; DATOPY=O; RATOPY=O; SMOKE=O; PACKS=99.99 

YEARS=99.99; YRSTOP=99.99; PYRS=-1.00; VISIT='04' 

00 TO 71 

GET NEXT REX:ORD 

80 CONTINUE 

00 TO 3 

HERE AT END OF FILE ON LINE 3 

100 CONTINUE 

CALL EXIT 

END 

*****************-********* 

SUBROUTINE ERROR( ID,MESSAG) 

*************************** 

TYPES OUT ERROR MESSAGE ON TTY WITH ALPHANUMERIC ID. 

MESSAGE MUST BE LONGER THAN 10 CHARACTERS TO WORK, OTHERWISE 

YOU MAY GET GARBAGE. 

DIMENSION MESSAG(2) 

DOUBLE PRECISION MESSAG 

TYPE 1, ID,MESSAG 

82 
03070 

03080 

03090 

03100 

03110 

03120 

03130 

C 

C 

C 

03140 C 

03150 

03160 

03170 

03180 

03190 

03200 

03210 

03220 

03230 

03240 

03250 

03260 

03270 

03280 

03290 

03300 

03310 

03320 

03330 

03340 

03350 

03360 

03370 

03380 

03390 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

1 FORMAT (/ 1 *** ER:ROR ID ',A4,': ',2A10) 

RETURN 

END 

**************************** 

SUBROUTINE EXCEPT(ID,MESSAG) 

**************************** 

TYPES 00T EXCEPTION MESSAGE ON TTY WITH ALPHANUMERIC ID. 

MESSAGE MUST BE LONGER THAN 10 CHARACTERS TO WORK, OTHERWISE 

YOU MAY GET GARBAGE. 

DIMENSION ME~SAG(2) 

DOUBLE PRECISION MESSAG 

TYPE 1, ID, MESSAG 

1 FORMAT (/ 1 EXCEPTION ID ',A4,': ',2A10) 

RETURN 

END 

************************** 

SUBROUTINE WARN(ID,MESSAG) 

************************** 

TYPES OUT WARNING MESSAGE ON TTY WITH ALPHANUMERIC ID. 

MESSAGE MUST BE LONGER TRAN 10 CHARACTERS TO WORK, OTHERWISE 

YOU MAY GET GARBAGE. 

DIMENSION MESSAG(2) 

OOUBLE PRECISION MESSAG 

TYPE 1, ID, MESSAG 

1 FORMAT(/' * WARNING ID 1 ,A4,': ',2A10) 

RETURN 

END 

83 

Listing of Computer Program to Edit Follow-up Interview 

00010 

00020 

00030 

C 

C 

C 

00040 C 

00050 

00060 

C 

C 

00070 C 

00080 

00090 

00100 

00110 

00120 

00130 

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00150 

00160 

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C 

C 

C 

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00390 

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00480 

00490 

00500 

00510 

C 

C 

C 

PROGRAM TO PROCESS T.D.I. FOLLOltl-UP INTERVIEWS 

(FORMERLY CALLED FOLUPB.FOR) 

WRITTEN BY LARRY JANESICI MARCH 21, 1978 

(WITH CODE SEX;MENTS FROM TDIINV.FOR) 

UPDATED BY RAY KERN MARCH, 1979 

790 

791 

792 

800 

801 

908 

IMPLICIT INTIDER (A-Z) 

COMMUN/RAND/MAXID,TABLE(1000,2) 

REAL PACKS,YEARS,YRSTP,AGE,S1,DIF,DMO,YEARSI,PACKSI,PLANTI 

REAL YRSIPI,PYRS,PYRSI 

DOUBLE PRECISION IFILE,OFILE,XFILE 

DIMENSION CC(80),0THER{5) 

FORMAT (A 10) 

FORMAT {A 1) 

FORMAT {A2) 

FORMAT {A4,74X,A2) 

FORMAT (80I1) 

FORMAT {A4,1X,3I2,6I2,2X,5I2,5X,F5.2,2I2,4F6.2,1X,3A2) 

INPUT AND OUTPUT FILES DETE:RMINED BY VISIT NUMBER 

TYPE 1 

1 FORMAT (/ 1 PROGRAM TO PROCESS T.D.I. FOLLCM-UP INTERVIEWS.') 

2 TYPE 3 

3 FORMAT (/' ENTER 2 DIGIT VISIT NUMBER (08,09,10) - 1 $) 

~CCEPT 792, !VISIT 

IF (IVISIT.EQ.'08 1 ) GOTO 4 

IF (IVISIT.EQ.'09') GOTO 5 

IF {IVISIT.EQ.'10') GOTO 6 

00 TO 2 

4 CONTINUE 

IFILE='TDI8.INV'1 OFILE='TDEXT8.INV' 

00 TO 7 

5 CONTINUE 

!FILE=' TDI9.INV' 7 OFILE=' TDEXT9.INV' 

00 TO 7 

6 CONTINUE 

IFILE=' TD110 .INV' 7 OFILE=' TDEXTX. INV' 

7 CONTINUE 

OPEN{UNIT=20,ACCESS='SE;?IN',FILE=IFILE) 

OPEN{UNIT=21,ACCESS='SE;?OUT',FILE=OFILE) 

RANDOM ACCESS ON T.D.I. BACKUP INTERVIEW EXTRAcr FILE 

XFILE = 'TDBAKI.INV'1 MAXID = 500 

CALL TABGEN (XFILE) 

OPEN(UNIT=01,ACCESS='RANDOM',RECORD SIZE=80,FILE=XFILE) 

TYPE 8 

8 FORMAT ( /' DO YOU WANT DATA EXTRACfED ( Y OR N)? ' $ ) 

85 
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c 

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C 

ACCEPT 791, !EXT 

IF (IEXT.EQ.'N') GO TO 11 

TYPE 9 

9 FORMAT ( 1 DO YOU WANT TDBAKI.INV UPDATED?'$) 

ACCEPT 791, !BAK 

11 CONTINUE 

READ20,800,END=100) ID,CARD 

IF (CARD.EQ. '06') GO TO 12 

CALL ERROR (ID, 'CARD OUT OF SEQUENCE' ) 

STOP 

12 CONTINUE 

BACKSPACE 20 

READ(20,801,END=100) CC 

MO= CC(05)*10 + CC(06) 

DA= CC(07)*10 + CC(08) 

YR= CC(09)*10 + CC(10) 

FETCH PREVIOUS INTERVIEW EXTRACT FROM BACK-UP EXTRACT FILE 

CALL GETREC(ID,N,RNF) 

READ(01#N,908) IDI,MOI,DAl,YRI,LRSI, 

*URSI,CBRONI,EBRONI,DYSPI,ATOPYI,OTHER,PLANTI,HAZOCI, 

*SMOKEI,PACKSI,YEARSI,YRSTPI,PYRSI,STUDYI,VISITI,RECRDI 

CHECK INTERVIEW DATE WITH PREVIOUS INTERVIEW DATE. 

SKIP ID IF ERROR. 

IF(RNF.EQ.1) GO TO 85 

IF(YR.GT.YRI) GO TO 15 

IF(YR.EQ.YRI.AND.MO.GT.MOI) GO TO 15 

CALL WARN (ID, 'DATE > PREVIOUS DATE') 

GO TO 85 

DETERMINE VISIT FROM INTERVIEW DATE AND CHECK IT. 

15 CONTINUE 

VISIT = '00' 

IF(YR.EQ.76.AND.MO.GE.11.AND.MO.LE.12) VISIT= '08' 

IF(YR.EQ.77.AND.K:>.GE.10.AND.MO.LE.11) VISIT= '09' 

IF(YR.EQ.78.AND.MO.EQ.10) VISIT= '10' 

IF(VISIT.EQ.IVISIT) GO TO 20 

BAD DATE - SKIP PROCESSING FOR THIS ID 

CALL WARN (ID, 1 FOLLOW-UP DATE' ) 

GO TO 85 

LOWER RESP. FINAL INTERVIEW 

20 CONTINUE 

86 
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01090 

01100 

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C 

C 

01150 C 

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01270 

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C 

LRS = 0 

IF (CC(13).EQ.1.0R.CC(14).EQ.1.0R.CC(16).EQ.1.0R.CC(17).EQ.1 

*.OR.CC(26).EQ.1.0R.CC(29).EQ.1.0R.CC(31).EQ.1) 

*LRS = 1 

IF (CC(13).EQ.2.AND.CC(14).EQ.2.AND.CC(16).EQ.2.AND. 

* CC(17).EQ.2,AND.CC(29).EQ,2,AND.CC(31).EQ.2.AND. 

* (CC(26).EQ.2.0R.CC(26).EQ.9)) 

*LRS = 2 

IF ( LRS • NE. 0 ) GO TO 2 5 

CALL EXCEPT (ID, 1 LCMER RESP. SYMPTOM 1 ) 

URS - FINAL INTERVIEW 

25 CONTINUE 

URS= 0 

IF (CC(34).EQ.1,0R.CC(36).EQ.1) URS= 1 

IF ((CC(34).EQ.2.0R.CC(34).EQ.9).AND.CC(36).EQ,2) URS= 2 

IF (URS. NE. 0) GO TO 30 

CALL EXCEPT (ID, 'UPPER RESP. SYMPTOM') 

BRON. - FINAL INTERVIEW 

30 CONTINUE 

COUGH=O; PHLEG=O; CBRON=O; EBRON=O 

IF ((CC(13).EQ.1.0R.CC(14).EQ.1).AND.CC(15).EQ.1) COUGH= 1 

IF ((CC(16).EQ.1oOR.CC(17).EQ,1).AND.CC(18).EQ.1) PHLEG = 1 

IF ((CC(13).EQ.1.0R.CC(13).EQ,2).AND. 

* (CC(14).EQ.1.0R.CC(14).EQ.2).AND. 

* (CC(15).EQ.2.0R.CC(15),EQ,9)) COUGH= 2 

IF ( (CC( 16) .EQ.1.0R.CC( 16) .EQ.2) .AND. 

* (CC(17).EQ.1.0R.CC(17).EQ.2).AND. 

* (CC(18).EQ.2.0R.CC(18).EQ,9)) PHLEG = 2 

IF (COU~.EQ.1.AND.PHLEG.EQ.1) EBRON= 1 

IF (COUGH.EQ.2.0R. PHLEG.EQ,2) EBRON= 2 

IF (EBRON.EQ.O) CALL EXCEPT (ID, 'CURRENT BRONCHITIS') 

DYSPNEA GRADE ( 1=NO, 2-5=YES) 

DYSP = 0 

CC25=CC(25); CC26=CC(26); CC27=CC(27); CC28=CC(28) 

IF (CC25.EQ.2.AND.CC26.EQ.9.AND.CC27.EQ.9.AND.CC28.EQ.9) DYSP=1 

IF (CC25.EQ.1.AND.CC26.EQ.2,AND.CC27.EQ.9.AND.CC28.EQ.9) 0SYP=2 

IF (CC25.EQ.1.AND.CC26.EQ.1.AND.CC27.EQ.2.AND.CC28.EQ.9) DYSP=3 

IF (CC25.EQ,1.AND.CC26.EQ.1,AND.CC27.EQ,1.AND.CC28.EQ.2) DYSP=4 

IF (CC25.EQ.1.AND.CC26.EQ.1.AND.CC27.EQ.1.AND.CC28.EQ.1) DYSP=S 

IF (DYSP.EQ.O) CALL EXCEPT (ID,'DYSPNEA GRADE') 

40 CONTINUE 

SMOKI'OO UPDATE 

SMOKE=O; PACKS=99.99; YEARS=99.99; YRSTP=99.99; PYRS=-1 .OO 

87 
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C 

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C 

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C 

C 

C 

C 

IF(CC(54).EQ.1.AND.CC(55).EQ.1) SMOKE= 1 

IF(CC(54).EQ.1.AND.CC(55).EQ.2.AND. 

* (CC(59).EQ.1.0R. CC(64).EQ.1)) SMOKE 2 2 

IF(CC(54).EQ.2.AND.CC(55).EQ.9.AND.CC(59).EQ.9.AND.CC(64).EQ.9) 

*SMOKE= 3 

IF (SMOKE.NE.0.AND.SMOKEI.NE.O) GO TO 50 

IF (SMOKEI.EQ.O) SMOKE= 0 

CALL EXCEPT (ID,'(F)SMOKING STATUS') 

GO TO 81 

DIF EQUALS DIFFERENCE BETWEEN FOLLOW-UP INTERVIEW 

AND THE PREVIOUS INTERVIEW IN YEARS. 

S1 IS THE # CIGARETTES SMOKED/DAY • 

50 CONTINUE 

DIE- = (YR-YRI)*360 + (MO-M0I)*30 + (DA-DAI) 

DIF = DIF /360. 

SI= CC(56)*10 + CC(57) 

IF((SMOKE.EQ.3.0R.SMOKE.EQ.2).AND. 

* (SMOKEI.EQ.2.0R.SMOKEI.EQ.3)) GO TO 79 

IF(SMOKE.EQ.1.AND.SMOKEI.EQ.1) GO TO 60 

IF((SMOKE.EQ.2.0R.SMOKE.EQ.3).AND. 

*(SMOKEI.EQ.1)) GO TO 65 

IF(SMOKE.EQ.1.AND.(SMOKEI.EQ.2.0R.SMOKEI.EQ.3)) 

*GO TO 70 

CIGARETTE SMOKER BOTH VISITS 

60 CONTINUE 

CDRRENT SMOKER LAST VISIT 

IF (YRSTPI.EQ.O.O) YEARS = DIF 

PAST SMOKER LAST VISIT 

IF (YRSTPI.GT.O.O.AND.YRSTPI.LT.99.99) YEARS= DIF/2. 

IF (S1.GT.O.AND.S1.NE.77.AND.S1.NE.88.AND.S1.NE.99) GO TO 62 

CALL EXCEPT(ID, "(F)PACKS/DAY SMOKED') 

GOTO 63 

62 PACKS= S1/20. 

63 YRSTP = 0 .O 

GO TO 80 

STOPPED SMOKING BETWEEN VISITS 

65 CONTINUE 

PACKS = PACKS I 7 SMOKE = SMOKE I 

IF (PACKS.EQ.99.99J CALL EXCEPT (ID,'(F)PACKS/DAY SMOKED') 

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C 

C 

C 

C 

C 

C 

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C 

C 

C 

C 

C 

C 

C 

C 

IF (YRSTPI.EQ.O.O) GO TO 66 

IF (YRSTPI.GT.O.O.AND.YRSTPI.LT.99.99) GO TO 67 

ERROR ON LAST VISIT YEARS STOPPED SMOKING 

CALL EXCEPT (ID,'(F)YRS STOPPED SMOKE') 

00 TO 80 

OJRRENT SMOKER LAST VISIT 

66 CONTINUE 

YEARS = DIF /2. 

YRSTP = DIF/2. 

00 TO 80 

PAST SMOKER LAST VISIT 

67 CONTINUE 

YEARS=0.07 PACKS-0.0 

YRSTP = YRSTPI + DIF 

IF (YEARS.EQ.99.99) CALL EXCEPT (ID,'(F)YEARS SMOKED') 

GO TO 80 

STARTED SMOKING BE'IWEEN VISITS 

70 CONTINUE 

IF(S1.GT.O.AND.S1.NE.77.AND.S1.NE.88.AND.S1.NE.99) GO TO 72 

CALL EXCEPT (ID,'(F)PACKS/DAY SMOKED') 

00 TO 73 

72 PACKS= S1/20. 

73 YRSTP = 0 .O 

YEARS = DIF/2. 

00 TO 80 

NEVER SMOKED IN EITHER VISIT 

79 CONTINUE 

PACKS = 0 .O 

YEARS = 0 .O 

YRSTP = 99.99 

IF (SMOKEI.EQ.2) SMOKE= 2 

00 TO 80 

PACK-YEARS UPDATE 

80 CONTINUE 

IF (PACKS.EQ.99.99.0R.YEARS.EQ.99.99) GO TO 81 

PYRS = PACKS*YEARS 

WRITE ON TO EXTRACrION FILE 

81 CONTINUE 

IF (IEXT.NE. 'Y') GO TO 85 

STUDY = 1 08' 

PLANT= 0.0 

HAZOCC = 0 

Rl!J:ORD = '0 8' 

89 
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C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

02910 C 

02920 

02930 

02940 

02950 

02960 

029,70 

02980 

03000 

03010 

03020 

03030 

03040 

03050 

C 

C 

C 

C 

C 

C 

C 

03060 C 

WRITE (21,908) ID,MO,DA,YR,LRS,URS,CBRON,EBRON,DYSP,ATOPY, 

*OTHER,PLANT,HAZOCC,SMOKE,PACKS,YEARS,YRSTP,PYRS, 

*STUDY,VISIT,RECORD 

BACK-UP EXTRAC'r FILE UPDATE 

IF (IBAK.NE. 1 Y1 ) GO TO 85 

WRITE (01#N,908) ID,MO,DA,YR,LRS,URS,CBRON,EBRON,DYSP,ATOPY, 

*OTHER,PLANT,HAZOCC,SMOKE,PACKS,YEARS,YRSTP,PYRS, 

*STUDY,VISIT,RECORD 

85 CONTINUE 

SKIP RECORD 20 

GO TO 11 

HERE ON END-OF-FILE 

100 CONTINUE 

CALL EXIT 

END 

*************************** 

SUBROUTINE ERROR(ID,MESSAG) 

*************************** 

TYPES 00T ERROR MESSAGE ON TTY WITH ALPHANUMERIC ID. 

MESSAGE MUST BE LONGER THAN 10 CHARAC'rERS TO WORK, OTHERWISE 

YOU MAY GET GARBAGE. 

DIMENSION MESSAG(2) 

DOUBLE PRECISION MESSAG 

TYPE 1, ID,MESSAG 

1 FORMAT (/ 1 *** ERROR ID ',A4,': ',2A10) 

RETURN 

END 

**************************** 

SUBROUTINE EXCEPT(ID,MESSAG) 

**************************** 

TYPES 00T EXCEPTION MESSAGE ON TTY WITH ALPHANUMERIC ID. 

MESSAGE MUST BE LONGER THAN 10 CHARAC'rERS TO WORK, OTHERWISE 

YOU MAY GET GARBAGE. 

DIMENSION MESSAG(~) 

DOUBLE PRECISION MESSAG 

TYPE 1, ID,MESSAG 

RETURN 

END 

*****************•******** 

SUBROUTINE WARN(ID,MESSAG) 

************************** 

90 
03070 

03080 

03090 

03200 

03110 

03120 

03130 

03140 

03150 

03160 

03170 

03180 

03190 

03200 

C 

C 

C 

C 

C 

C 

C 

03210 C 

03220 

03230 

03240 

03250 

03260 

03270 

03280 

03290 

03300 

03310 

03320 

03330 

03340 

03350 

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03370 

03380 

03390 

03400 

03410 

03420 

03430 

03440 

03450 

03460 

03470 

03480 

03490 

03500 

03510 

03520 

Q3530 

03540 

03550 

03560 

03570 

03580 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

TYPES OUT WARNING MESSAGE ON TTY WITH ALPHANUMERIC ID. 

MESSAGE MUST BE LONGER THAN 10 CHARACTERS TO WORK, OTHERWISE 

YOU MAY GET GARBAGE. 

DIMENSION MESSAG(2) 

DOUBLE PRECISION MESSAG 

TYPE 1, ID MESSAG 

1 FORMAT(/' * WARNING ID ',A4,': ',2A10) 

RETURN 

END 

************************* 

SUBROUTINE TABGEN (!FILE) 

************************* 

GENERATES LOOK-UP TABLE FOR RANDOM ACCESS BASED ON S~UENTIAL 

SCAN FOR ID# - PAIRS ID# WITH RECORD #. THIS SUBROUTINE SHOULD 

BE CALLED ONLY ONCE. 

CALLING S~UENCE: CALL TABGEN(IFILE) 

WHERE !FILE = INTEX;ER, DOUBLE PRECISION VARIABLE CONTAINING NAME 

OF FILE TO BE SCANNED. 

IN THE LABELLED COMK>N /RAND/: 

MAXID = INTEX;ER VARIABLE CONTAINING MAX # OF CASES (ID#' S). 

MUST BE LESS THAN 1000 (LINEAR DIM OF TABLE ARRAY). 

TABLE( 1000,2) =- 2-D INTFnER ARRAY LINKING ID# WITH ITS RECORD # 

IN FILE. 

IMPLICIT INTEX;ER (A-Z) 

DOUBLE PRECISION !FILE 

COMK>N /RAND/ MAXID, TABLE(1000,2) 

800 FORMAT (A4) 

900 FORMAT (/' ERROR IN SUBROUTINE TABGEN: ') 

901 FORMAT(' ID ',A4,' HAS APPEARED TWICE IN DATA FILE ',A10. 

*',RECORD# ',16 1 AND ',16,'.') 

90 2 FORMAT ( ' # OF CASES > MAX # SET UP FOR TABLE. ' ) 

INITIALIZATION 

OPEN (UNIT=1,ACCESS= 1 S~IN' ,FILE=IFILE) 

IF(MAXID.LE.O) MAXID = 1000 

DO 10 1=1,MAXID 

TABLE(I,1)= 1 0000' 

TABLE(I,2)=0 

10 CONTINUE 

I = 0 

N = 0 

ID2 = •ooo• 

91 
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03610 

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03630 

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C 

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C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

C 

04010 C 

04020 

04030 

040.ilO 

04050 

04060 

04070 

04080 

04090 

C 

LOOP UNTIL YOU FIND A DIFFERENT ID. N IS THE RECORD#. 

100 CONTINUE 

N = N+1 

READ (1,800,END=999) ID1 

IF(ID1.EQ.!D2) GO TO 100 

HERE TO MAKE TABLE ENTRIES. 

CHECK IF ID HAS BEEN ENTERED BEFORE. 

200 CONTINUE 

DO 300 K=1,I 

IF (TABLE(K,1).NE.ID1) GO TO 300 

TYPE 900 

TYPE 901, ID1,IFILE,TABLE(K,2),I 

STOP 

300 CONTINUE 

I = I+1 

TABLE(I,1) = ID1 

TABLE(I,2) = N 

ID2 = ID1 

CHECK IF INDEX > MAX. OONTINUE SCAN IF NOT. 

IF (I.LE.MAXID) GO TO 100 

TYPF. 900 

TYPE 902 

STOP 

HERE ON EOF FOR CLOSE-OTJT. 

999 OONTINUE 

CLOSE (UNIT=1) 

RETURN 

END 

*************************** 

SUBROUTINE GETREC(ID,N,RNF) 

*************************** 

SEARCHES TABLE GENERATED BY SUBROUTINE TABGEN FOR ID# AND 

RETRIEVES RECORD # FOR RANDOM ACCESS. 

IMPLICIT INTJ!X;ER (A-Z) 

OOMK>N /RAND/ MAXID,TABLE(1000,2) 

:RNF = 0 

DO 10 I=1,MAXID 

IF(TABLE(I,1).NE.ID) GO TO 10 

N = TABLE(I,2) 

RETURN 

92 
04100 

04110 

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04130 

04140 

04150 

04160 C 

04170 C 

04180 

04190 C 

04200 C 

04210 C 

04220 C 

04230 

04240 

04250 

04260 

04270 

10 CONTINUE 

TYPE 900, ID 

900 FORMAT(/' RECORD NOT FOUND FOR ID ',A4) 

RNF = 1 

RETURN 

END 

********************************* 

SUBROUTINE AERR)R(ID,MESG1,MESG2) 

********************************* 

TYPES OUT ERR'.>R MESSAGE ON TTY WITH ALPHANUMERIC ID 

DOUBLE PRECISION MESG1 ,MESG2 

TYPE 900, ID,MESG1 ,MESG2 

900 FORMAT (/ 1 ERROR ID ',A4,': ',2A10) 

RETURN 

END 
References 

1. Cotes, J.E.: Lung Function Assessment and Application in Medicine. 

Blackwell Scientific Publications, 1975, Oxford. 

2. Knudson, R.J., Slatin, R.C., Lebowitz, M.D., and Burrows, B.: 

The Maximal Expiratory Flow-Volume Curve - Normal Standards, 

Variability, and Effects of Age. Amer.Rev.Resp.Dis. 113, 

587-600, 1976. ~ 

3. Fletcher, C., Peto, R., Tiner, c., and Speizer, F.: The Natural 

History of Chronic Bronchitis and Emphysema. Oxford University 

Press, 1976, Oxford. 

4. Berry, G.: Longitudinal Observations, Their Usefulness and Limitations with Special Reference to the Forced Expiratory Volume. 

Bull. Physio-path. resp., 10, 643-655, 1974 

5. Berry, G,, McKerrow, C.B., Molyneux, M.K.B., Rossiter, C.E., 

Tombleson, J,B.C.: A study of acute and chronic changes in 

ventilatory capacity of workers in Lancashire cotton mills. 

Brit.J.Industr.Med.: 30, 25-36, 1973. 

6. Butcher, B.T., Jones, R.N., O'Neil, C.E., Glindmeyer, H.W., Diem, J.E., 

Dharmarajan, V., Weill, H. and Salvaggio, J.E.: Longitudinal study 

of workers employed in the manufacture of toluene diisocyanate. 

Amer.Rev.Resp.Dis., 116, 411-421, 1977. 

7. Weill, H., Salvaggio, J., Neilson, A., Butcher, B.T., and Ziskind, M.: 

Respiratory effects in toluene diisocyanate manufacture: A multidisciplinary approach. Env. Health Perspectives, 11, 101-108, 1975. 

8. Butcher, B.T., Salvaggio, J.E., Weill, H. and Ziskind, M.M.: Toluene 

diisocyanate (TD!) pulmonary disease: Immunologic and inhalation 

challenge studies. J. Allergy Clin.Immunol., 58, 89-100, 1976. 

9. Butcher, B. T.: Immunologic aspects of toluene diisocyanate (TDI) 

sensitivity in exposed workers at a TD! plant. Proceedings of the 

Fifth Annual Workshop of the Asthma and Allergic Disease Centers. 

Pub. NIAID, U.S.D.H.E.W. pp. 171-175, 1975. 

10. Butcher, B.T.: 

cyanate (TDI). 

Inhalation challenge testing with toluene diisoJ, Allergy Clin.Immunol., (In Press) 1979. 

94 
11. Butcher, B.T., Karr, R.M., O'Neil, C.E., Wilson, M.R., Dharmarajan, V., 

Salvaggio, J.E. and Weill, H.: Inhalation challenge and pharmacologic 

studies of toluene diisocyanate (TDI) sensitive workers. J. Allergy 

Clin. Immunol. 64, 146-152, 1979. 

12. Butcher, B.T., Salvaggio, j.E., O'Neil, C.E., Weill, H. and Garg, O: 

Toluene diisocyanate (TDI) pulmonary disease: Immunopharmacologic 

and mecholyl challenge studies. J, Allergy Clin. Immunol. ~. 

223-230, 1977. 

13. Butcher, B.T. and Karr, R.M.: TDI induced asthma, in "Diagnosis and 

management of industrial, drug and radiation hazards - selected 

topics." Volume 1. Grune and Stratton. (In Press), 1979. 

14. Davies, R.J., Butcher, B.T., O'Neil, C.E. and Salvaggio, J.E.; 

The in vitro effect of toluene diisocyanate on lymphocyte cyclic 

adenosine monophosphate production by isoproterenol, prostaglandin 

and histamine -- a possible mode of action. J, Allergy Clin. Immunol. 

60, 233-239, 1977. 

15. Beaven, M.A., Jacobsen, S. and Horakova, Z: Modification of the 

enzymatic isotopic assay of histamine and its application to 

measurement of histamine in tissues, serum and urine. Clin. Chim. 

Acta,]]_, 91, 1972. 

16. Karr, R.M., Davies, R.J., Butcher, B.T., Lehrer, S.B., Wilson, M., 

Dharmarajan, V., and Salvaggio, J.E.: Allergy Grand Rounds -

Occupational Asthma. J. Allergy Clin. Immunol., 61, 54-65, 1978. 

17. Mitchell, J.C. and Jordan, W.P.: Allergic contact dermatitis from 

radish, Raphanus saturis. Brit. J. Dermatol. 91, 183-189, 1974. 

18. Butcher, B.T., O'Neil, C/E., Karr, R.M., Weill, H., and Salvaggio, J.E.: 

Longitudinal study of isocyanate sensitive worker with concurrent 

development of food allergy shows loss of pharmacologic and methacholine reactivity. (In preparation). 

19. Karol, M.H., Ioset, M.M., and Alarie, i'.''.C.; Tolyl-.specific IgE 

antibodies in workers with hypersensitivity to toluene diisocyanate. 

Am. Ind. Hyg. Assoc. J., 39, 454, 1978. 

20. Butcher, B.T., O'Neil, C.E. and Salvaggio, J.E.: Radioallergosorbent 

testing (RAST) of TDI reactive individuals using p-tolyl-isocyanate 

(TMI) antigen. J. Allergy Clin. Immunol., (Submitted), 1979. 

95 
21. Weill, H., Salvaggio, J., Neilson, A., Butcher, B., and Ziskind, M.; 

Respiratory effects in toluene diisocyanate manufacture: A multidisciplinary Approach. Environ. Hlth. Perspect. 11, · 101--108, 1975. 

22. Butcher, B.T., Jones, R.N., O'Neil, C.E., Glindmeyer, H.W., Diem, J.E., 

Dharmarajan, V., Weill, H., and Salvaggio, J.E.: Longitudinal study 

of workers employed in the manufacture of toluene diisocyanate • 

. Am. Rev. Resp. Dis., 116, 411-421, 1977. 

23. Dharmarajan, V.: Analysis of TDI and MDI in air. Am.Ind.Hyg.Assoc.J., 

38, 725, 1977. 

24. Dharmarajan, V., Weill, H., and Self, C.W.: Environmental characterization of toluene diisocyanate in a manufacturing plant. Am. Ind. 

Hyg. Assoc. J., 39, 414-418, 1978. 

25. Neilson, A. and Booth, K.S.: A technique for dynamic calibration of 

a continuous toluene diisocyanate monitor. Am. Ind. Hyg. Ass·oc. J. 

36, 169-171, 1975. 

26. Dharmarajan, V. and Rando, R.J. A new method for the generation of 

standard atmospheres of organo isocyanates. Am. Ind. Hyg. Assoc. J, 

(In Press), 1979. 

27. Dharmarajan, V.: Occupational exposures to methylene bisphenylisocyanate (MDI): Gaseous or aerosol? J, Environ. Pathol. and Toxicol. 

l, 1-8, 1979. 

28. Marcali, K.: Microdetermination of toluene diisocyanate in atmospheres. 

Anal. Chem.~. 552-558, 1957. 

29. Reilly, D.A.: A test-paper method for the determination of toluene 

diisocyanate vapor in air. Analyst,~ 178-185, 1968. 

30. Allshuller, A.P. and Cohen, I.R.: Application of diffusion cells to 

the production of known concentrations of gaseous hydrocarbons. 

Anal. Chem., 32, 802-810, 1960. 

31. Model 7000 TDI Monitors are distributed in U.S.A. by MDA Scientific, 

Inc., 808 Busse Highway, Park Ridge, Ill., 60068. 

32. Dixon, W.J.: BMDP, Biomedical Computer Programs, University of 

California Press, Berkeley, 1975. 

33. IMSL Reference Manual, Edition 6, International Mathematical and 

Statistical Libraries, Houston, 1977. 

96 
34. Graybill, Franklin A.: An Introduction to Linear Statistical Models 

Vol 1, McGraw-Hill Book Company, Inc., 1961, New York. 

35. Kauffmann, F., Drouet, D., Lellouch, J., and Brille, D.: Twelve years 

spirometric changes among Paris area workers. Int. Journ. of Epid. ~, 

201-202, 1979. 

36. Ferris BG, Chen H, Puleo Sand Murphy R L H. Chronic Non specific 

Respiratory Disease in Berlin, New Hampshire, 1967 to 1973. A further 

Follow-up study. American Review of Respiratory Disease 114, 475, 1976. 

37. Higgins ITT, Gilson JC, Ferris BG, Waters ME, Campbell Hand 

Kiggins· M w·. IV. Chronic respiratory disease in an industrial town: 

a nine-year follow-up study. Preliminary Report. American Journal 

of Public Health 58: 1667, 1968. 

38. Petty TL, Pierson DJ, Dick NP, Hudson L D and Walker SH. 

Follow-up evaluation of a prevalence study for chronic bronchitis 

and Chronic Airways Obstruction. American Review of Respiratory 

Disease 114: 881, 1976. 

39. Lebowitz MD. Longitudinal changes in lung function and respiratory 

symptoms. Paper presented IEA Meeting, Puerto Rico, SepteUlher 1977. 

40. Pham Q T, Benis A M, Muir J M, Sadoul and Haluska J. Follow-up study 

of construction workers with obstructive lung disease. Scandinavian 

Journal of Respiratory Diseases 58:215, 1977. 

97 
\D 

00 

Visit Date 

Number Added 

Permanently Lost 

Eligible from Previous 

Visit 

Total Eligible 

Refused 

(% of Elig. from Prev.) 

Temporarily Lost 

(% of Elig. from Prev.) 

Complete Spirometry 

(% of Total Eligible) 

Complete Spirometry 

(% of Eligible -

Refused - Temp. Lost) 

4-73 11-73 

168 27 

- 6 

- 162 

168 189 

0 3 

(1.9) 

2 11 

(1.2) (6.8) 

144 145 

(85.7) (76.7) 

144 145 

(86. 7) (82.8) 

Tpble 1 

PARTICIPATION BY VISIT 

SPIROMETRY 

9-74 3-75 10-75 

25 34 23 

9 3 11 

180 202 225 

205 236 248 

7 12 21 

(3. 9) (5.9) (9.3) 

13 21 17 

(7. 2) (10.4) (7. 6) 

168 197 200 

(81. 9) (83.5) (80.6) 

168 197 200 

(90.8) (97. 0) (95.2) 

3-76. 11-76 12-77 10-78 TOTAL 

- - - - 277 

13 7 13 9 71 

235 228 215 206 

235 228 215 206 

25 37 35 36 

(10. 6) (16. 2) (16.3) (17.5) 

24 25 34 29 

(10.2) (11. O) (15.8) (14 .1) 

175 161 142 135 

(74.5) (70.6) (66.0) ( 65. 5) 

175 161 142 135 

(94.1) (97. 0) (97.3) (95.7) 
Table 2 

DESCRIPTIVE STATISTICS AT INITIAL VISIT 

FOR THE 274 MALE PARTICIPANTS 

1. Race: 

2. Cigarette Smoking: 

3. Atopy (positive to 2 or 

more skin tests) 

4. Upper respiratory symptoms 

5. Lower respiratory symptoms 

6. Bronchitis 

7. Dyspnea 

8. Age (years) 

9. Height (inches) 

10. Pack-years 

11. IgE IU/ml 

12. FEV% P(l) 

13. FVC% P 

14. FEF25_75% P 

15. RV% P 

16. TLC% P 

17. DLco% P 

18. K% P 

85% 

51.1% 

22.6% 

25.9% 

20.1% 

38.7% 

29.6% 

3.6% 

84.3% 

11.7% 

2.9% 

274 

274 

273 

271 

244 

244 

244 

217 

217 

212 

212 

white 

current 

Ex 

Never 

Atopic 

Positive 

Positive 

Positive 

GRADE I 

GRADE II 

GRADE III 

Mean 

35.9 

69.9 

14.37 

181.8 

100.2 

102.7 

91.0 

99.4 

101.0 

99.0 

99.7 

274 

273 

274 

273 

272 

273 

271 

Standard 

Deviation 

11.3 

2.56 

16.3 

287.7 

13.3 

12.3 

26.5 

25.7 

11.6 

16.7 

17.3 

(l)% predicteds are taken from the pulmonary function measurements at the 

time of the initial interview or the next visit at which the pulmonary 

function measurement was taken if it was not done at the visit of the 

initial interview. 

99 
Table 3 

DESCRIPTIVE STATISTICS (in ppm) 

FOR 8-HOUR TIME-WEIGHTED AVEP-~GES 

8-Hour Time-Weighted Averages 

Used to Develop Exposure Categories 

"Turnaround Time" 

8-Hour Time-Weighted Averages 

MAX 

P75 

MEAN 

MEDIAN 

p25 

MIN 

S. D. 

GEO. MEAN 

GEO. S. D. 

n (samples) 

.0250 

.0036 

.0035 

.0020 

.0011 

.0001 

.0045 

.0020 

2.94 

1949 

100 

.0250 

.0067 

.0055 

.0030 

.0020 

.0001 

.0059 

.0036 

2.55 

144 
Table 4 

JOB TITLES BY TIME-WEIGHTED 

AVERAGE EXPOSURE CATEGORY 

Number 

Exposure Job of 

Category Code Job Location Samples 

HIGH 13001 C Operator TDI 222 

15050 E Operator Drumming 199 

15051 E Operator Tank Farm 5 

31030 Millwright Phosgene 12 

33030 Welder Phosgene 1 

MODERATE 1001 Foreman TDI 239 

12001 B Operator TDI 208 

14030 D Operator Phosgene 224 

30001 Unsp. Maint. TDI 7 

30021 Unsp. Maint. Machine Shop 4 

31001 Millwright TDI 51 

32001 Boilermaker TDI 17 

33001 Welder TDI 31 

34001 Pipefitter TDI 30 

36001 Instruments TDI 7 

36019 Instruments Shop 5 

41002 Unspec. Sampl. TDI Lab 7 

42002 A Sampler TDI Lab 14 

43002 B Sampler TDI Lab 7 

LOW 1014 Foreman Soda Ash 4 

1017 Foreman TlOl 4 

11001 A Operator TDI 69 

11010 A Operator TDA 60 

12020 B Operator Hyco 88 

13010 C Operator TDA 89 

13040 C Operator POL-DNT 14 

14040 D Operator POL-DNT 124 

15010 E Operator TDA 35 

15030 E Operator Phosgene 1 

19052 Operator Bug Pond 99 

31012 Millwright Sodium Nitrate 2 

33009 Welder Ammonia 6 

33027 Welder Pilot Plant 3 

35001 Electrician TDI 15 

35018 Electrician Shop 6 

36009 Instruments Ammonia 6 

37028 Carpenter Shop 4 

40002 Chemist TDI Lab 15 

53029 Clerical CAR Warehouse 2 

57012 Truck Driver Sodium Nitrate 4 

58012 Warehouseman Sodium Nitrate 5 

71021 Machinist Shop 4 

101 
Table 5 

8-HOUR TIME-WEIGHTED AVERAGE DESCRIPTIVE 

STATISTICS (in ppm) BY EXPOSURE CATEGORY 

CATEGORY HIGH MODERATE LOW 

MAX. .0250 .0250 .0248 

p75 .0088 .0035 .0020 

MEAN .0068 .0032 .0016 

MEDIAN .0050 .0020 .0013 

p25 .0025 .00130 .0007 

MIN. .0001 .0001 .0001 

s. D. .0062 .0039 .0018 

GEO. MEAN .0045 .0020 .0011 

GEO. S. D. 2.69 2.68 2.37 

n 439 851 659 

102 
Category I: 

Category II: 

Category III: 

Category IV: 

Table 6 

JOB TITLES BY PEAK EXPOSURE CATEGORY 

15050 

30001 

31030 

33030 

12001 

13001 

31001 

33001 

34001 

01001 

14030 

15051 

32001 

37001 

42002 

01014 

01017 

11001 

11010 

12020 

13010 

13040 

14040 

15010 

15030 

19052 

30021 

31010 

31012 

33009 

33010 

33020 

33027 

35001 

35018 

36001 

36009 

36019 

36020 

36030 

37028 

38001 

39001 

40002 

41002 

43002 

53029 

57012 

58012 

71021 

E Operator in Drumming 

Unspecified Maintenance in TDI 

Millwright in Phosgene 

Welder in Phosgene 

B Operator in TDI 

C Operator in TDI 

Millwright in TDI 

Welder in TDI 

Pipe Fitter in TDI 

Foreman in TDI 

D Operator in Phosgene 

E Operator in TK Farm 

Boilermaker in TDI 

Carpenter in TDI 

A Sampler in TDI Lab 

Foreman in Soda Ash 

Foreman in T-101 

A Operator in TDI 

A Operator in TDA 

B Operator in HYCO 

C Operator in TDA 

C Operator in POL-DNT 

D Operator in POL-DNT 

E Operator in TDA 

E Operator in Phosgene 

Operator in Bug Pond 

Unspecified Maint. in 

Machine Shop 

Millwright in TDA 

Millwright in Sodium Nitrate 

Welder in Ammonia 

Welder in TDA 

Welder in HYCO 

Welder in Pilot Plant 

Electrician in TDI 

Electrician in Electric Shop 

Instruments in TDI 

Instruments in Ammonia 

Instruments in Instr. Shop 

Instruments in HYCO 

Instruments in Phosgene 

Carpenter in Carpenter Shop 

Insulator in TDI 

Maint. Supervisor in TDI 

Chemist/Analyst in TDI Lab 

Unspecified Sampler in TDI Lab 

B Sampler in TDI Lab 

Clerical in CAR Warehouse 

Truck Driver or Laborer in 

Sodium Nitrate 

Warehouseman in Sodium Nitrate 

Machinist in Machine Shop 

103 
Table 7 

Percentage of Time Spent Above Selected Concentration 

Levels by Peak Exposure Category 

Percentage of time above: 

Number of 

Category .005 ppm .01 ppm .02 ppm .04 ppm .06 ppm .08 ppm Samples 

I 36.1 20.1 10.6 5.5 3.9 3.4 219 

II 24.0 12.1 5.0 2.4 1.6 1.4 618 

III 10.7 4.0 1.4 0.5 0.3 0.2 518 

IV 3.2 0.7 0.3 0.1 0.1 0.0 738 

All Categories 

Combined 14.6 6.9 3.0 1.4 1.0 0.8 2093 

104 
Table 8 

ANNUAL CHANGE REGRESSION COEFFICIENTS(!) USING CUMULATIVE EXPOSURE, 

ATOPIC STATUS AND PACK-YEARS AS EXPLANATORY VARIABLES 

FEV1 L/yr 

FVC L/yr 

FEV% (yr)-l 

FEF25_75 L/sec-yr 

FEF50 L/sec-yr 

-1 K (min-nunHg-yr) 

ml 

DLco min-nunHg-yr 

E.V L/yr 

TLC L/yr 

(RV/TLC) x 100 (yr)-l 

n 

223 

223 

223 

223 

223 

164 

164 

179 

179 

179 

Cumulative 

Intercept Exposure 

-.0103 

(-1.09) 

-.0039 

(-. 40) 

-.2041 

(-1. 52) 

-.0736 

(-3.23) 

-.1115 

(-3. 50) 

-.169 

(-4.99) 

-1.127 

(-4. 97) 

.0391 

(3.09) 

.0275 

(1. 81) 

.4400 

(3.04) 

-.0770 

(-.81) 

.0455 

(: 47) 

-1. 372 

(-1. 01) 

-.00275 

(-1.19) 

-.000386 

(-.12) 

1. 276 

(3. 31) 

7.926 

(3. 07) 

-.126 

(-.99) 

.00371 

(. 02) 

-1.112 

(-. 77) 

Atopy 

.0011 

( .15) 

-.0070 

(-. 97) 

.1246 

(1. 21) 

.0249 

(1.44) 

.0374 

(1. 54) 

-.0155 

(-.58) 

-.433 

(-2.43) 

-.00222 

(-. 24) 

-.0106 

(-.93) 

-.0181 

(-.17) 

PackYears 

-.00057 

(-2.55) 

-.00071 

(-3.13) 

-.00332 

(-1.03) 

-.00024 

(-.43) 

-.00036 

(-.48) 

-.00072 

(-. 85) 

-.0015 

(-. 27) 

.00104 

(3.58) 

.00048 

(1. 38) 

.0114 

(3.44) 

% Variability 

Explained 

7.36 

20.3 

3.0 

4.1 

6.5 

28.8 

47.5 

30.9 

5.5 

46.4 

(l)The numbers in parentheses are the regression coefficients divided by their standard 

errors. They should be compared to normal distribution percentiles for tests of 

significance. 

105 
Table 9 

ANNUAL CHANGE REGRESSION COEFFICIENTS(l) USING DICHOTOMIZED 

CUMULATIVE EXPOSURE, ATOPIC STATUS, AND PACK-YEARS AS EXPLANATORY VARIABLES 

Cumulative(2) 

Exposure Pack- % Variability 

n Intercept Category II Atopy Years Explain eel 

FEVl L/yr 223 -.0120 -.0118 .0009 -.00058 9.4 

(-2.14) (-1. 82) ( .13) (-2.60) 

FVC L/yr 223 -.0006 .0012 -.0069 -.00071 19.2 

(-.10) ( .19) (-.95) (-3.17) 

FEV% (yr) -1 223 -.2358 -.2024 .1216 -.0034 6.30 

(-2.94) (-2.20) (1.19) (-1.08) 

FEF25-75 L/sec-yr 223 -.0801 -.0406 .0243 -.00025 11.1 

(-5. 96) (-2.63) (1.42) (-.46) 

FEF50 L/sec-yr 223 -.1031 -.0285 .0373 -.00041 6.6 

(-5.44) (-1. 31) (1. 55) (-.54) 

K (min-mmHg-yr) -1 164 -.0934 .0518 -.00642 -.00101 16.3 

(-4.39) (1. 97) (-.24) (-1.19) 

' ml 

DLco min-mmHg-yr 164 -.6578 .3246 -.3755 -.0033 33.6 

(-4.64) (1. 86) (-2.09) ('-. 58) 

RV L/yr 179 .0286 -.0061 -.00289 .00107 27.1 

(3.83) (-. 07) (-.31) (3.67) 

TLC L/yr 179 .0278 .0000 -.0105 .00048 5.6 

(3.11) (.00) (-.93) (1.38) 

(RV/TLC) x 100 (yr)-l 179 .3331 .0313 -.0246 .0117 41. 7 

(3.93) (.32) (-. 23) (3.52) 

(1) (1) See Footnote of Table 8. 

<

2) Cumulative Exposure Category II has value if qJIDulative exposure is > • 0682 ppm-months 

and O otherwise. Thus, its coefficient estimates the difference between the two categories after controlling for the other variables. 

106 
Table 10 

ANNUAL CHANGE REGRESSION COEFFICIENTS(l) USING THREE CU}!ULATIVE 

EXPOSURE CATEGORIES(2), ATOPIC STATUS, AND PACK-YEARS AS EXPLANATORY VARIABLES 

Cwnulative( 2) Cumulative( 2) 

Exposure Exposure Pack- % Variabilit 

n Interce2t Category II A Categorv II B Ato2:z Years Exelained 

FEV1 L/yr 223 -.0123 -.0187 .0132 .0020 -.00057 13 . .:: 

(-2.21) (-2.25) (1. 31) (. 28) (-2.59) 

FVC L/yr 223 -.0008 -.0049 .0115 -.0060 -.00072 21.1 

(-.15) (-. 56) (1.10) (-.82) (-3.17) 

FEV% (yr) -1 223 -.2374 -.2339 .0597 .1262 -.0034 7.0 

(-2.97) (-1.95) (.41) (1.23) (-1. 07) 

FEF25-75 L/sec-yr 223 -.0806 -.0494 .0166 .0256 -.00024 13.0 

(-6.00) (-2.46) (.68) (1. 49) (-. 44) 

FEF50 L/sec-yr 223 -.1032 -.0304 .0035 .0377 -.00041 6.7 

(-5.44) (-1.07) (.10) (1.56) (-. 54) 

-1 K unin-mmHg-yr )_ 164 -.0921 -.0308 .1407 -.00870 -.00107 35.1 

(-4.46) (-.·86) (3.26) (-. 33) (-1.29) 

ml 

DLco m~n-mmHg-yr 164 -.6468 -.208 .9013 -.3892 -.00370 66.1 

(-4.68) (-. 86) (3.12) (-2.22) (-. 67) 

RV L/yr 179 .0288 .00467 -.00951 -.00334 .00107 27.1 

(3.85) (.40) (-. 69) (-. 35) (3. 65) 

TLC L/yr 179 .0276 -.00860 .0154 -.00978 .00049 5.5 

(3.10) (-. 62) (.94) (-. 87) (1.40) 

(RV/TLC) x 100 (yr)-l 179 .3359 .1122 -.1455 -.0312 .0117 43.8 

(3. 97) (.86) (-. 93) (-.29) (3.51) 

(l)See Footnote (l) of Table 8. 

(

2)cumulative Exposure Category II A has value 1 if cumulative exposure is >.0682 ppm-months and O otherwise. 

Cumulative Exposure Category II B has value 1 if cumulative exposure is >.1 ppm-months and O otherwise. The 

coefficient of Cumulative Exposure Category II A (resp. Cumulative Exposure Category II B) estimates the 

difference between the two lowest (resp. highest) categories after controlling for the other variables. 

107 
Table 11 

ANNUAL CHANGE REGRESSION COEFFICIENTS(l) USING TIME ABOVE .02 ppm, 

ATOPIC STATUS, AND PACK-YEARS AS EXPLANATORY VARIABLES 

Time Above Pack- % Variability 

n Intercept .02 ppm Atopy Years Explained 

FEV1 L/yr 223 -.0141 -.0043 .0010 -.00057 9.51 

(-2.51) (-1.05) ( .14) (-2.56) 

FVC L/yr 223 -.0020 .0032 -.0070 -.00071 19.7 

(-. 35) (. 75) (-. 96) (-3.12) 

FEV% L/yr 223 -.2470 -.452 .1231 -.0035 6.2 

(-3.09) (-1. 93) (1. 24) (-1.08) 

FEF25-75 L/sec-yr 223 -.0853 -.0184 .0246 -.00024 7.6 

(-6. 31) (-1.83) (1. 42) (-. 44) 

FEF50 L/sec-yr 223 -.1107 -.0066 .0375 -.00038 4.7 

(5.83) (-. 47) (1. 55) (-. 50) 

K (min-mmHg-yr)-1 164 -.0968 .0380 -.00832 -.00095 16.6 

(-4. 47) (2.14) (-. 31) (-1.10) 

ml 

DLco 164 -.6482 .1761 -.382 -.00305 - min-mmHg-yr - 27.3 

(-4.45) (1. 48) (-2.11) (-.53) 

RV L/yr 179 .0361 -.0129 -.0017 .00102 38.1 

(4. 93) (-2.38) (-.19) (3.55) 

TLC L/yr 179 .0322 -.00733 -.00996 .00045 9.9 

(4.69) (-1.11) (-. 88) (1.29) 

(RV/TLC) x 100 (yr) -1 179 .4238 -.1361 -.0114 .0112 55.4 

(5. 08) (-2. 20) (-.11) (3.40) 

(l)See Footnote (l) of Table 8. 

108 
Table 12 

ANNUAL CHANGE REGRESSION COEFFICIENTS(l) USING DICHOTOMIZED 

TIME ABOVE .02 ppm, ATOPIC STATUS, AND PACK-YEARS AS EXPLANATORY VARIABLES 

Peak Exposure(2) Pack- % Variability 

n Intercept Category II Atopy Years Explained 

FEV1 L/yr 223 -.0127 -.0108 .00058 -.00058 10.9 

(-2.29) (-1.64) (.08) (-2.61) 

FVC L/yr 223 .0005 -'.0015 -.0069 -.00072 18.6 

( .09) (-.22) (-. 95) (-3.18) 

FEV% yr 

-1 223 -.2594 -.1541 .1158 -.0034 6.0 

(-3. 26) (-1. 63) (1.13) (-1.07) 

FEF25-75 L/sec-yr 223 -.0847 -.0317 .0232 -.00024 10.0 

(-6. 34) (-1.99) (1. 35) (-.45) 

FEF50 L/sec-yr 223 -.0999 -.0396 .0.361 -.00045 8.7 

(-5.34) (-1. 77) (1. 50) (-. 60) 

K (min-mrnHg-yr) -1 164 -.0977 .0646 -.0058 -.00101 24.3 

(-4.64) (2.50) (-.22) (-1.19) 

ml 

DLco min-mmHg-yr 164 -.6560 • 3170 -.3706 -.00338 31. 4 

(-4, 64) (1. 82) (-2.06) (-.60) 

RV L/yr 179 .0341 -.0172 -.00285 .00104 32.4 

(4.69) (-1. 92) (-. 30) (3.60) 

TLC L/yr 179 .0331 -.0158 -.0105 .00045 11. 3 

(3.81) (-1.48) (-. 94) (1. 31) 

(RV/TLC) x 100 (yr) -1 179 , 3911 -.1427 -.0240 .0115 44.2 

(4. 70) (-1.40) (-. 22) (3.46) 

(l)See Footnote (1) of Table 8. 

(2)Peak Exposure Category II has value 1 if time above .02 ppm is> .19 months and O otherwise. Thus, its coefficient estimates the difference between the two categories after 

controlling for the other variables. 

109 
Table 13 

ANNUAL CHANGE REG~SSION COEFFICIENTS(l) USING THREE TIME ABOVE 

.02 ppm CATEGORIES, ATOPIC STATUS, AND PACK-YEARS AS EXPLANATORY VARIABLES 

Peak Exposure Peak Exposure Pack- i; Variability 

n Intercept Category II A Category II B Atopy Years Explained 

FEV1 L/yr 223 -.0127 -.0139 .0070 .00042 -.00057 10. 7 

(-2. 30) (-1. 71) (.65) (.06) (-2. 57) 

FVC L/yr 223 .0003 -.0088 .0167 -.0073 -.00071 18.5 

(.06) (-1.05) (1.49) (-1. 00) (-3.11) 

FEV% (yr) -1- 223 -.2581 =.0972 -.0129 .1185 -.0035 6.3 

(-3.25) (-.84) (-. 84) (1.16) (-1.11) 

FEF25-75 L/sec-yr 223 -.0847 -.0303 -.0031 .0233 -.00024 9.9 

(-6. 34) (-1.55) (-.12) (1. 35) (-. 46) 1--' 

1--' 

0 FEF50 L/sec-yr 223 -.1005 -.0682 .0660 .0345 -.00037 11. 7 

(-5. 40) (-2.50) (1. 80) (1. 44) (-.49) 

-1 K 164 -.0975 .0687 -.00979 -.0054 -.00102 24.3 (min-mmHg-yr) 

(-4. 63) (2.16) (2. 24) (-. 20) (-1. 21) 

ml 

DLco 164 -.6541 .3615 -.1051 -.3670 -.00357 36.0 min-mm."'lg-yr (-4.62) (1. 69) (-. 36) (-2.05) (-.63) 

RV L/yr 179 .0345 -.00661 -.0242 -.00166 .00100 39.5 

(9. 81) c....:. 61) (-1.63) (-.18) (3.48) 

TLC L/yr 179 .0332 -.0128 -'.00679 -.0102 .00044 12.5 

(3.83) (-. 97) (-. 38) (-. 91) (l.2z} 

(RV/TLC) x 100 (yr)-l 179 . 3952 -.00866 -.3102 -.00783 .0109 57.8 

(4.84) (-. 07) (-1.82) (-.07) (3.33) 

(1) (1) See Footnote of Table 8 

(Z)Peak Exposure Category II A has value 1 if time above .02 ppm> .19 months and O otherwise. Peak Exposure 

Category II B has value of time above .02 ppm> 1 month and O otherwise. Thus, the coefficient of peak 

Exposure Category II A (resp., Peak Exposure Category II B) estimates the difference between the two lowest 

(resp. highest) categories after controlli~g for the other variables. 
Table 14 

ESTIMATED POPULATION MEAN ANNUAL CHAi.~GES AND OTHER STATISTICS 

Estimated Percent of(l) 

Standard Residual Degrees of Total Variability 

Estimated Standard Deviation Error Freedom in Due to True 

Mean Annual Error of Mean of True Annual Standard Residual Sum Annual 

n Change Annual Change Cha~ge Deviation of Sguares Change 

FEV1 L/yr 223 -.0244 .00316 .0255 .1326 928 49.5 

FVC L/yr 223 -.0121 .00330 .0272 .1372 928 51.0 

FEV% (yr) -1 223 -.3928 .0451 .3985 1. 7752 928 57.1 

FEF25-75 L/sec-yr 223 -.0928 .00762 ,0598 .3242 928 47.5 

.... FEF50 L/sec-yr 223 -.1100 .0106 .0790 .4653 928 43.3 .... 

.... 

K (min-mmHg-yr) -1 164 -.0947 .0123 .0757 .3651 301 53.2 

ml 

DL CO min-nnn..llg-yr 164 -. 7160 .0834 .4629 2.559 301 46.4 

RV L/yr 179 .0435 .00434 .0306 .1616 448 48.6 

TLC L/yr 179 :0322 .00498 .0328 .1910 448 43.9 

(RV/TLC) x 100 (yr)-l 179 .5121 .0495 .2925 1.980 448 36.6 

(l)Percent of total variability due to true annual change for a participant with usable data at all nine visits. 

For a participant present at fewer than nine visits, the percent of total variability due to true annual c' ange 

will be smaller. 
Table 15 

Summary Statistics on 274 Participants by Number of 

Visits with Complete Spirometry 

Number of Number of 

visits ~3 visits <3 

n 226 48 

% White 85.4 83.3 

% Lower Respiratory Symptoms 29.8 29.8 

% Upper Respiratory Symptoms* 42.0 23.4 

% Bronchitis 3.5 4.3 

% Interview Atopic 33.8 25.5 

% Atopic* 23.0 6.3 

% Dyspnea 14.3 17.0 

% Current Cigarette Smokers 50.9 53.2 

Number of visits ~3 Number of visits 

Standard (1) Standard 

Mean Deviation n Mean Deviation 

Age (years) 35.6 11.0 226 35.5 12.6 

Height (inches) 70.0 2.5 226 69.8 2.9 

Pack-years 13.7 14.9 226 17.4 21.9 

FEV1 % P(2) 100.4 13.4 207 99.2 13.3 

FVC % p 102.9 12.4 207 101.4 12.0 

FEF % p 91.5 26.9 207 88.2 24.5 

RV% P 99.3 25.2 186 100.4 28.8 

TLC% P 101.3 11.6 186 99.5 11.6 

K % p 99.7 17.7 181 99.7 14.2 

Cumulative Exposure* 

(ppm-months) .0725 .0354 225 .0231 .0169 

Time above 

.02 ppm (months)* .55 • 72 225 .29 .33 

*p <.05 

(l)n represents number of participants with usable data. 

<3 

n 

48 

48 

47 

37 

37 

37 

31 

31 

31 

30 

30 

(2) % predicteds are taken from the pulmonary function measurement at the time of 

the initial interview or the next visit at which the pullllonary function measurement was taken if it was not done at the visit of the initial interview. 

112 
FEV% 

n 

ml/yr 

ml/yr 

(yr)-1 

FEF25_75 ml/sec-yr 

FEF50 ml/sec-yr 

Table 16 

ESTIMATED MEAN ANNUAL CHANGES 

IN SPIROMETRIC TESTS BY 

TWO CUMULATIVE EXPOSURE CATEGORIES 

FOR NON-ATOPICS WITH 

14 PACK-YEARS OF SMOKING 

GROUP I 

(ppm-months~ .0682) 

149 

-20 

-11 

-0.28 

-84 

-109 

(p = .034>1 

(p = 1.0) 

(p, = .014) 

(p = • 004) 

(p = • 095) 

GROUP II 

(ppm-months> .0682) 

74 

-32 

-9 

-.48 

-125 

-137 

1 p-values are significance levels for one-tailed tests of significance for differences 

between the two groups after controlling for other variables. 

113 
Table 16A 

Descriptive Statistics at Entry to Study 

by Cumulative Exposure Category 

n 

Race(% White) 

Age (years) 

Height (inches) 

Smoking (% current cigarette) 

(% ex-cigarette) 

(% never) 

% LRS 

% URS 

% Bronchitis 

Dyspnea (% Grade I) 

(% Grade II) 

(% Grade III) 

% Atopic 

Cumulative 

Exposure 

~.0682 ppm-months 

149 

84.1 

37.6 ± 11.0 

69.8 ± 2.5 

114 

51.0 

24.8 

24.2 

31. l 

46.4 

4.6 

83.3 

12.7 

4.0 

21.9 

Cumulative 

Exposure 

>.0682 ppm-months 

74 

87.8 

31. 7 ± 9. 8 

70.3 ± 2.4 

50.0 

21.6 

28.4 

27.4 

33.8 

1.4 

90.4 

8.2 

1.4 

25.7 
C 

I 

G 

A 

R 

'.E 

T 

T 

E 

s 

M 

0 

K 

I 

N 

G 

never 

ex 

Table 16B 

FEV1 Slope (ml/year)* by Smoking Exposure Category 

Controlling for Age and FEV1 Level 

Exposure 

:'.::. 0682 

ppm-months 

1 

n = 35 

-12 

n = 31 

-26 

>.0682 

ppm-months 

-37 

n = 21 

-15 

n = 16 

-37 

FEV1 level 

FEV /h3 <55 1 

Exposure 

~.0682 

ppm-months 

>.0682 

ppm-months 

-18 -57 

n = 1 n = 0 

-32 -35 

n = 6 n = 0 

-46 -57 

current 

n = 64 n = 35 n = 12 n = 2 

*Cells means were estimated using the multiple regression procedure described in 

the text. This procedure used age as one of the covariates. The cells means 

presented above are adjusted to the average age (35.6 years) of the study group. 

Tests of Significance 

(1) age effect -5.8 ml/decade one-tailed p-value = .03 

(2) low FEV1 effect -20 ml/year one-tailed p-value = .04 

(3) exposure effect in never smokers -38 ml/year one-tailed p-value = .001 

(4) Smoking effect in ~.0682 exposure category 

exsmoker - never smoker effect -13 ml/year one-tailed p-value = .12 

current smoker - ex-smoker effect -14 ml/year one-tailed p-value = .06 

current smoker-never smoker effect -27 ml/year one-tailed p-value = .004 

115 
Table 17 

ESTIMATED MEAN ANNUAL CHANGES IN FEV1, FEV%, AND 

FEF25_75 BY CUMULATIVE EXPOSURE FOR NON-ATOPICS WITH 14 PACK-YEARS OF SMOKING 

GROUP I GROUP II A GROUP II B 

(ppm-months S.0682) ( .0682 < ppm-months S.1) (ppm-months 

n 149 37 37 

FEV1 ml/yr -20 (p = .025) 1 -39 (p = .19) -26 

FEV% (yr) -1 -.29 (p = .OS) -.52 (p = .68) -.46 

FEF25_75 ml/sec-yr -84 (p = .014) -133 (p = .50) -117 

(l)p-values are significance levels for differences between adjacent categories 

after controlling for other variables. 

116 

> .1) 
Table 18 

ESTIMATED MEAN ANNUAL CHANGES IN SPIROMETRIC TESTS 

BY TWO TIME ABOVE .02 ppm CATEGORIES 

FOR NON-ATOPICS WITH 14 PACK-YEARS OF SMOKING 

GROUP I GROUP II 

(months S.19) (months >.19) 

n 140 83 

FEV1 -21 (p = .051) 1 -32 

FVC -10 (p = .413) -11 

FEV% -.31 (p = .052) -.46 

FEF25-75 -88 (p = • 023) -120 

FEF50 -106 (p = .038) -146 

(l)p-values are significance levels for one-tailed tests of 

significance for differences between the two groups after 

co~trolling for the other variables. 

117 
n 

FEV1 ml/yr 

FEV% (yr) -1 

Table 19 

ESTIMATED MEAN ANNUAL CHANGES IN FEV1 , FEV%, 

FEF25_75 , AND FEF50 BY TIME ABOVE .02 ppm 

CATEGORY FOR NON-ATOPICS WITH 14 PACK-YEARS OF SMOKING 

GROUP I GROUP II A 

(months ~.19) (.19 < months ~1) 

140 47 

-21 (p = .087) -35 (p = .52) 

-.31 (p = .40) -.40 (p = .40) 

FEF25-75 ml/sec-yr -88 (p = .12) -118 (p = .90) 

FEF50 ml/sec-yr -106 (p = .012) -174 (p = .072) 

GROUP II B 

(months >1) 

36 

-28 

-.42 

-121 

-108 

(l)p-values are significance levels for differences between adjacent categories 

after controlling for other variables. 

ll8 
Table 20 

SUMMARY STATISTICS ON 274 PARTICIPANTS BY NUMBER 

OF VISITS WITH COMPLETE DIFFUSING CAPACITY 

DETERMINATIONS 

Number of Visits 

~3 

Number of Visits 

<3 

n 

% White 

% Lower Respiratory Symptoms 

% Upper Respiratory Symptoms* 

% Bronchitis 

% Interview Atopy 

% Atopic 

% Dyspnea 

% Current Cigarette Smokers 

165 

88.5 

29.3 

46.7 

4.2 

34.5 

24.8 

14.6 

48.5 

109 

80.7 

30.6 

26.9 

2.8 

29.0 

12.7 

14.9 

55.6 

Number of Visits ~3 

Standard (1) 

Number of Visits <3 

Standard 

Mean 

Age (years) 36.0 

Height (inches) 70.1 

Pack-years 14.0 

FEV1% P(2) 100.7 

FVC % P 103.2 

FEF % P 91.1 

RV% P 100.0 

TLC% P 102.0 

K % P 99.9 

Cumulative Exposure* 

(ppm-months) .068 

Time above .02 ppm 

(months) .49 

Deviation 

11.0 

2.5 

15.0 

12.7 

12.1 

26.1 

24.5 

11. 7 

17.4 

.031 

.67 

n 

165 

165 

165 

151 

151 

151 

139 

139 

135 

164 

164 

Mean Deviation 

35.9 

69.7 

14.9 

99.5 

101.8 

90.9 

99.0 

100.0 

99.4 

.039 

.42 

11.8 

2.6 

18.2 

14.4 

12.7 

27.4 

27.9 

11.5 

17.1 

.023 

.49 

* p < .05 

(1) n represents the number of participants with usable data. 

n 

109 

109 

108 

93 

93 

93 

78 

78 

77 

77 

77 

<

2)% predicteds are taken from the pulmonary function measurement at the time 

of the initial interview or the next visit at which the pulmonary measurement 

was taken if it was not done at the visit of the initial-interview. 

119 
Table 21 

SUMMARY STATISTICS ON 274 PARTICIPANTS BY NUMBER OF 

VISITS WITH COMPLETE LUNG VOLUME DETERMINATIONS 

Number of Visits Number of Visits 

:::3 <3 

n 182 92 

% White 87.4 81.5 

% Lower Respiratory Symptoms 28.7 31.9 

% Upper Respiratory Symptoms* 44.0 28.6 

% Bronchitis 3.8 3.3 

% Interview Atopy 34.1 28.9 

% Atopic 24.2 12.0 

% Dyspnea· 13.3 17.7 

% Current Cigarette Smokers 48.4 57.1 

Number of Visits ~3 Number of Visits 

Standard (1) Standard 

Mean Deviation n Mean Deviation 

Age {years) 35.7 11.0 182 36.5 11.9 

Height (inches) 70.1 2.5 182 69.5 2.6 

Pack-years 13.5 14.8 182 16.2 19.0 

FEV

1

%(2) 101.3 12.9 165 98.0 14.0 

FVC % p 103.6 12.3 165 100.8 12.3 

FEF % p 92.0 25.9 165 88.9 28.0 

RV% P 98.8 24.6 151 100.9 28.3 

TLC % p 101. 7 11.6 151 99.5 11.6 

K % p 99.5 17.4 146 100.2 17.1 

Cumulative Exposure* 

(ppm-months) .08 .03 181 .03 .02 

Time Above • 02 ppm 

(months) .57 .75 181 .38 .45 

*p ~ .05 

(l)n represents the number of participants with usable data. 

<3 

n 

92 

92 

91 

79 

79 

79 

66 

66 

66 

60 

60 

(

2)% predicteds are taken from the pulmonary function measurement at the time 

of the initial interview or the next visit at which the pulmonary function 

measurement was taken if it was not done at the visit of the initial interview. 

120 
Table 22 

SUMMARY STATISTICS ON 274 PARTICIPANTS BY 

COMPLETENESS OF INITIAL AND FINAL INTERVIEW 

Complete Incomplete 

n 203 71 

% White 87.1 80.3 

% Interview Atopy 37.0 30.4 

% Atopic 22.2 14.1 

% Current Cigarette Smokers 52.2 48.6 

Complete Incomplete 

Standard (1) Standard 

Mean Deviation n Mean Deviation 

Age (years) 35.4 10.8 203 37.5 12.6 

Height (inches) 69.9 2.6 203 69.9 2.4 

Pack-years 13.6 14.8 203 16.5 20.1 

FEV1% p(2) 100.5 13.4 182 99.5 13.4 

FVC % p 103.1 12.0 182 101.6 13.2 

FEF % p 91.4 27.2 182 89.8 24.6 

RV% P 98.6 25.8 165 102.2 25.7 

TLC % p 101.5 11.5 165 99.7 11.9 

K % p 100.1 16.9 160 98.7 18.6 

Cumulative Exposure* 

(ppm-months) .082 .033 202 .013 .015 

Time Above .02 ppm* 

(months) . 62 .80 202 .019 .19 

* p < .05 

(l)n represents the number of participants with usable data. 

n 

71 

71 

70 

62 

62 

62 

52 

52 

52 

23 

23 

(

2)% predicteds are taken from the pulmonary function measurements at the time 

of the initial interview or the next visit at which the pulmonary function 

measurement was taken if it was not done at the visit of the initial interview. 

121 
Last 

Initial Usable Zero 

INTRVW INTRVW PK-YRS 

YES YES 7 

u 

YES NO 0 

R 

NO YES 3 

s 

NO NO 6 

YES YES 1 

L 

YES ·NO 0 

R 

NO YES 2 

s 

NO NO 13 

YES E YES 0 

B 

YES NO 0 

R 

NO YES 1 

0 

NO NO 15 

N 

YES D YES 0 

y 

YES NO 1 

s 

NO YES 1 

NO p NO 14 

Table 23 

LONGITUDINAL C~GE IN SYMPTOMS 

BY CUMULATIVE EXPOSURE CATEGORY 

Cumulative Exposure~ .0682 

Non-Atopic Atopic 

0-15 > 15 Zero 0-15 > 15 Zero 

Cumulative Exposure> .0682 

Non-Atopic Atopic 

0-15 > 15 Zero 0-15 

PK-YRS PK-YRS PK-YRS PK-YRS PK-YRS TOTAL PK-YRS PK-YRS PK-YRS PK-YRS PK-YRS 

15 20 2 4 3 51 2 5 10 3 4 

3 0 2 1 0 6 1 0 1 0 0 

9 7 2 6 1 28 8 8 3 2 2 

9 11 2 0 3 31 9 14 6 1 4 

8 9 0 5 2 25 1 2 5 1 4 

7 4 3 1 1 16 0 7 0 0 0 

10 7 1 1 1 22 3 3 6 0 0 

11 18 4 4 3 53 16 15 9 5 5 

0 0 0 1 0 1 0 0 0 0 0 

5 1 0 0 0 6 0 1 0 0 0 

0 5 0 1 0 7 1 2 1 1 1 

31 32 8 9 7 102 19 24 19 5. 9 

5 5 0 0 0 10 1 3 2 0 0 

1 2 1 2 0 7 0 0 3 0 0 

3 5 2 1 1 13 1 4 5 1 2 

27 26 5 8 6 86 18 20 10 5 7 

122 

>15 

PK-YRS TOTAL 

1 25 

1 3 

0 23 

1 35 

1 14 

0 7 

1 13 

1 51 

0 0 

0 1 

1 7 

2 78 

0 6 

0 3 

2 15 

1 61 
Last 

Initial Usable 

INTRVW INTRVW 

YES YES 

u 

YES NO 

R 

NO YES 

s 

NO NO 

YES YES 

L YES NO 

R 

NO YES 

s 

NO NO 

YES E YES 

B 

YES NO 

R 

NO YES 

0 

NO NO 

N 

YES D YES 

y 

YES s NO 

NO p YES 

N 

NO E NO 

A 

Table 24 

LONGITUDINAL CHANGE IN SYMPTOMS 

BY TIME ABOVE .02 ppm CATEGORY 

Time above .02 ppm ~ 0.19 Time above .02 > 0.19 

Non-Atopic Atopic Non-:-Atopic A;opic 

Zero 0-15 >15 Zero 0-15 >15 Zero 0-15 >15 Zero 0-15 

PK-YRS PK-YRS PK-YRS PK-YRS PK-YRS PK-YRS TOTAL PK-YRS PK-YRS PK-YRS PK-YRS PK-YRS 

6 16 22 3 5 3 55 3 4 8 2 3 

0 2 0 2 1 1 6 1 1 1 0 0 

4 10 7 2 5 1 29 7 7 3 2 3 

9 11 11 2 1 3 37 6 12 6 1 3 

2 6 8 1 4 3 24 0 4 6 0 5 

0 9 4 3 1 1 18 0 5 0 0 0 

2 9 9 1 1 1 23 3 4 4 0 0 

15 15 19 4 6 3 62 14 11 8 5 3 

0 0 0 0 1 0 1 0 0 0 0 0 

0 4 1 0 0 0 5 0 2 0 0 0 

1 0 5 1 1 0 8 1 2 1 0 1 

18 35 34 8 10 8 113 16 20 17 5 8 

0 4 6 0 0 0 10 1 4 1 0 0 

1 1 2 1 1 0 6 0 0 3 0 1 

2 3 5 2 1 2 15 0 4 5 1 2 

16 31 27 6 10 6 96 16 16 9 4 5 

123 

>15 

PK-YRS TOTAL 

1 21 

0 3 

0 22 

1 29 

0 15 

0 5 

1 12 

1 42 

0 0 

0 2 

1 6 

- 1 67 

0 6 

0 4 

1 13 

1 51 
Table 24A 

Prevalences for Selected Respiratory Symptom Complexes 

at the Initial and Final Interviews 

by Smoking-Cumulative Exposure Categories 

Bronchitis Never Smokers Current or Ex-Smokers 

Mean 

n Initial Final Age n Initial Final 

~.0682 ppm-months 24 0% 4.2% 36.2 92 7.6% 7.6% 

>.0682 ppm-months 26 0% 7.7% 28.2 60 1. 7% 8.3% 

Dyspnea Never Smokers Current or Ex-Smokers 

Mean 

n Initial Final Age n Initial Final 

~.0682 ppm-months 24 8.3% 12.5% 36.2 92 16.3% 21. 7% 

>.0682 ppm-months 26 3.8% 11.5% 28.2 59 13.6 30.5% 

124 

Mean 

Pack- Mean 

Years Age 

20.0 38.9 

15.6 33.1 

Mean 

Pack- Mean 

Years Age 

20.0 38.9 

15.6 33.1 
Table 25 

"Clinical Reactors" to TDI 

Time in 

Smoking in Atopic Known Plants 

Age Pack-Years Challenge .?2 Skin Major Before Job When 

I. D. in 1973 <Initial) Results Test Exposure Symptoms Became Symptomatic Comments 

0033 47 47 - 0 + <1 week B Op TDI transferred out of TDI, 

then resigned from plant 

0035 26 7 0 0 7 months D Op TDI still works in TDI 

0037 27 7 + 0 0 2 months D Op TDI transferred out of TDI 

then quit for medical 

reasons 

0045 53 11 0 0 "weeks" Foreman TDA transferred out of TDI 

0046 26 6 - + + <2 months Chemical Engineer, resigned from plant 

East Zone 

0110 30 8 - + + 4 months Welder TDI/TDA transferred out of TDI 

0179 20 0 + 0 3 years C Op TDA still works in TDI 

0187 26 0 + + 4 months Pipefitter TDI/TDA transferred out of TDI 

0197 61 0 - 0 + 4 months Pipefitter TDI/TDA resigned from plant 

0200 32 0 0 0 2~ years Pipefitter TDI/TDA transferred out of TDI 

0218 57 0 0 0 3 months Insulator TDI/TDA transferred out of TDI 

0256 33 7 0 + 2 years Pipefitter TDI/TDA transferred out of TDI 

125 
Table 26 

TDI Environmental Exposure Evaluation (8/73 to 7/75) 

Location 

TDI Plant 

TDI Drumming Building 

Percent Weekly 

TWA Excursions 

Above .005 

82.7% 

60.3% 

126 

Percent Weekly 

TWA Excursions 

Above 0.02 

24.7% 

6.4% 
January 7 

January 14 

January 21 

January 28 

February 6 

February 13 

February 20 

February 27 

March 6 

March 13 

March 20 

March 27 

April 5 

April 12 

April 19 

April 26 

May 3 

May 10 

May 17 

May 24 

Table 27 

PERSONNEL MONITORING SCHEDULE 

(January 7 - May 28, 1976) 

thru January 11 "A" Shift 

thru January 18 "B" Shift 

thru January 25 "C" Shift 

thru February 1 "D" Shift 

thru February 10 "D" Shift 

thru February 17 "A" Shift 

thru February 24 "B" Shift 

thru March 2 "C" Shift 

thru March 10 "C" Shift 

thru March 17 "D" Shift 

thru March 24 "A" Shift 

' thru March 31 "B" Shift 

thru April 9 Maintenance 

thru April 16 Maintenance 

thru April 23 Maintenance 

thru April 30 Maintenance 

thru May 7 Drumming Lab 

thru May 14 Drumming Lab 

thru May 21 Drumming Lab 

thru May 28 Drumming Lab 

127 

4 p.m. - 12 a.m. 

4 p.m. - 12 a.m. 

4 p.m. - 12 a.m. 

4 p.m. - 12 a.m. 

8 a.m. - 4 p.m. 

8 a.m. - 4 p.m. 

8 a.m. - 4 p.m. 

8 a.m. - 4 p.m. 

12 a.m. - 8 a.m. 

12 a.m. - 8 a.m. 

12 a.m. - 8 a.m. 

12 a.m. - 8 a.m. 

8 a.m. - 4 p.m. 

8 a.m. - 4 p.m. 

8 a.m. - 4 p.m. 

8 a.m. - 4 p.m. 

8 a.m. - 4 p.m. 

8 a.m. - 4 p.m. 

8 a.m. - 4 p.m. 

8 a.m. - 4 p.m. 
Table 28 

COMPARISON OF TDI MONITOR VS. PERSONAL MONITOR 

Exposure in Minutes Time-

.005 .Cl "" .04 .06 no Total weighted 

Plant Date • v, .vu Name oom. avera2e Shift 

Area TDI 5-19-75 101.2 32.2 0 0 0 0 .0349 .0044 8 AM 

4 PM 

Production TDI 5-19-75 324 306 270 207 192 189 .200 .025 8 AM 

Worker 1 4 PM 

Production TDI 5-19-75 168 87 54 9 0 0 .054 .0068 8 AM 

Worker 2 4 PM 

Area TDI 5-20-75 16.1 11.5 0 0 0 0 .0139 ,0017 8 AM 

4 PM 

Production Unknown 5-20-75 195 162 120 39 0 0 .090 .0113 8 AM 

Worker 1 4 PM 

Production TDI 5-20-75 330 174 93 39 24 21 .105 .0131 8 AM 

Worker 2 4 PM 

Area TDI 5-22-75 0 0 0 0 0 0 .0104 .0013 8 AM 

4 PM 

Production Unknown 5-22-75 407 384 183 39 9 0 .154 .0193 8 AM 

Worker 1 4 PM 

Production TDI 5-22-75 327 138 48 15 9 9 .080 .010 8 AM 

Worker 2 4 PM 

Area TDI 6-25-75 200.1 140.3 87.4 20.7 0 0 .124 .0155 4 PM 

11 PM 

Production TDI 6-25-75 4 PM 

Worker 1 11 PM 

Production TDI 6-25-75 12 0 0 0 0 0 .019 .0024 4 PM 

Worker 2 11 PM 

Production TDI 6-25-75 9 0 0 0 0 0 .018 .0023 4 PM 

Worker 3 11 PM 

Area TDI 6-26-75 190.9 165.6 115 20.7 13.8 13.8 .1213 .0152 4 PM 

11 PM 

Production TDI 6-26-75 69 15 0 0 0 0 .020 .0025 4 PM 

Worker 1 11 PM 

Production Phosgene 6-26-75 36 6 0 0 0 0 .002 .00025 4 PM 

Worker 2 11 PM 

Production TDI 6-26-75 207 84 15 0 0 0 .047 .0059 4 PM 

Worker 3 11 PM 

Production TDI 6-26-75 51 21 6 0 0 0 .036 .0045 4 PM 

Worker 4 11 PM 

Area Drumming 5-20-75 400.2 299 69 43.7 41.4 41.4 .1490 .0186 8 AM 

4 PM 

Production Drumming 5-20-75 309 72 45 9 0 0 .066 .0083 8 AM 

Worker 1 4 PM 

Production Drumming 5-20-75 174 48 0 0 0 0 .036 .0045 8 AM 

Worker 2 4 PM 

Production Drumming 5-20-75 51 30 0 0 0 0 .022 .0028 8 AM 

Worker 3 4 PM 

Area Drumming 5-23-75 11.5 6,9 0 0 0 0 .0297 .0037 8 AM 

4 PM 

Production Drumming 5-23-75 8 AM 

Worker 1 4 PM 

Production Drumming 5-23-75 360 6 0 0 0 0 .050 .0063 8 AM 

Worker 2 4 PM 

Production Drumming 5-23-75 21 0 0 0 0 0 .016 .002 8 AM 

Worker 3 4 PM 

128 
Job Title 

Phosgene 

Operator 

TD! 

Operator 

DNT 

Operator 

Maintenance 

*Shift 1 

Shift 2 

Table 29 

SUMMARY OF PERSONAL MONITORING FOR PHOSGENE 

IN A TD! MANUFACTURING PLANT 

Monitoring Number Number 

Period of of 

Location Month-Year Shifts* Workers Readings 

Phosgene 3/76-12/76 1,2,3 10 71 

Plant 

TD! 3/76- 4/76 1,3 2 6 

Plant 

TDA 3/76 3 3 14 

Plant 

TD! and 5/76-12/76 1 6 22 

Phosgene 

Plant 

8 a.m. - 4 p.m. 

4 p.m. -12 midnight 

Shift 3 12 midnight - 8 a.m. 

129 

Concentration of 

Phosgene - PPM 

Mean 8-hr 

TWA + 

- SD 

0.004 + 0.004 -

0.004 + 0.003 

0.004 + 0.003 

0.011 + 0.017 -
HISTOGRAM OF 8-HOUR 

TIME-WEIGHTED AVERAGES 

(LOG-SCALE) 

40 

30 

20 

10 

Histogram of 1949 

a-Hour TimeWeighted Averages 

Used to Develop 

Exposure Categories 

~ o~~~~~~~...-~-

Q5 

~ 

~ 

Histogram of 144 

II , II Turn Around Time 

"' 40 a-Hour Time -

30 Weighted Averages 

20 

10 

oL....,JmJ!IJd~~~~'fA--

I 2 3 4 5 6 7 8 

Category of Log ( TWA ) 

Figure 1 

130 
HISTOGRAM OF 8-HOUR 

TIME-WEIGHTED AVERAGES 

BY EXPOSURE CATEGORY 

( LOG SCALE) 

40 

30 

20 

10 

High Exposure 

( 439 samples) 

o Lm,:,,1/ZJ.~~~~~L 

40 

......._ 30 

~ 

Moderate Exposure 

( 851 samples } 

~ 20 

rt 10 

oL....r;;Plm~~~~~~L40 

30 

20 

10 

Low Exposure 

( 659 samples) 

0 I--.&.~ ~~l'&lV&tlma.--....--

I 2 3 45 67 8 

Category of Log ( TWA ) 

Figure 2 

131 
FEV1 MEAN BY VISIT FOR THE 33 PARTICIPANTS 

WITH COMPLETE SPIROMETRY AT ALL NINE VISITS 

4.3 

4.2 

4.1 ~ 

~ 

l( 4.0 

3.9 

3.8 

Mean Annual Change = - .021 I / year 

4/73 11/73 9/74 I 10/75 I 11/76 12/77 10/78 

3/75 3/76 

Visit Date 

Figure 3 

132 
TD I REACTORS 

! FEv,I 

~ FEV1 

! ID 01911

4

"1 '75 

3.5~ 

3.0 • •, 

FEF2s-1!i 

(L/s~cl FEF25-15 

45~ .5 '75 ~ 

4.0 • 

~~., 4.5K • 

[!§"oo] j ~31- ' ' ' • 2 

'76 3 '76 

• ~ • •• ~ -- • • •1 • 

'75 ~ 'fr 'is I I I I '74 '74 '75 '76 '77 '78 

4.J 

j10021eJ~~ 

Year Year 

• ""8n to *" al ,_, from TDI 

Figure 4 

133 

TOI REACTORS 

~ 

~ FEV1 

110 0033 J :it._.._ 

;~ 

3. _.1.'73 .~ 

.... 

~ 

~ 

'73 

FEF2s-75 

2.0 1

1 I I I I I 

3/ 2 .+ -- 1~1111 

1, .... ,::~ 

I 

'78 3 

1,000..Jl· • • • • •. 2 

2. • 

2 I I I I I 1.5 11 I I I e, 

!tD of10].4 

~ ~ 

~& I 

,,._ ~ '75 '76 '77 78 

~ Year 

'~ '74 

5.0~ 

4.5 1 

pre- '74 °75 '76 '77 '78 

8JIP.OSU'9 

'73 

Year 

~ Nf9r1 to date of removql from TD I 
TDI REACTORS 

~ 

~ FEV1 

FEF25-75 

(L/sec) 

5.5 

FEF 25-75 

I I 5.5~ '14 5.o 

ID 0035 5.o ~ .1. VJ • 4.5 I • ------------• 

• . . . . . . . 

4.5 •, I I I I I 4.0 

7.0 ·16 1

76 

~ 5.] • I 6.5 'V 

j ID O 179 I • - • • 

5.0 8 •• • e 6,0 • e • 

4.5 I I I I I i 5.5 

pre- 174 175 176 '77 178 179 pre- 174 175 176 177 178 179 

exposure exposure 1

73 173 Year Year 

} refers to date of sensitization to TD I 

Figure 5 

134 
ce:o F G E 

D 

C 

............ . . 

. . H . : ' .......... 

J 

FIGURE 6 

SCHEMATIC DIAGRAM OF PROVOCATIVE 

INHALATION CHALLENGE CHAMBER 

135 

A= challenge subject 

B = observer 

C = TDI monitor 

D = air pump 

E = rotameter 

F = TDI container 

G = circulation fan 

H = exhaust (overhead) 

J = air lock 
A. 

,..,oo 

.., 

IL 

I so 

% 

u 

C. 

I 50 

% 

u 

IIIEIIATE IESPIISE 

I 2 3 4 5 6 

TIME AFTER CHALLENGE 

(HOURS) 

DIAL IESPOISE 

.. ~ 

2345678~ 

TIME AFTER CHALLENGE 

(HOURS) 

8. 

D. 

~-100 

IL 

Ill I 50 

C 

% 

u 

Figure 7 

LATE IESNISE 

I 2 3 4 5 

TIME AFTER CHALLENGE 

(HOURS) 

DOSE IESNISE 

~0.0lppm 

J r, 

23456 24 

TIME AFTER CHALLENGE 

(HOURS) 

Respiratory Response to Provocative Inhalation 

Challenge with TD! 

136 
EFFECT OF CROMALYN ON TOI INDUCED ASTHMA 

401 

30~ 

,-. FEF (25-75) 20 ~ 

Liter~nd 

. 

10 I 

0 

sec 

! I I 

IOO 

~~---______ I A • / --.........---- ~, 

\ I f--.o... ' __....____ -~------ Pl.MD> '\ \ \\ l 

I I 

20 IO O 0 

IEFORE BPT 

BPT 

~ 

10 20 30 

Time In Minutes 

Figure 8 

137 

AFTER 

BPT 

~~IO 

~ Cont~I [: 

~ TOI ~t ..... I 20 

0 

40 50 ., 

°lo 
z 

0 2 

t-

<{ 

...J 

:) 

::E 

tCl) 

~ 

::E 

<{ 

u 

0 ~ 150 

1000 

500 

IS 0 

N N 

R 

R 

10-BM ,o-4M 10-BM I0-4M 

TD I 

N 

R - TOI REACTORS 

N = NORMALS 

Figure 9 

Cyclic Adenosine Monophosphate Dose Response 

Slopes of TDI Reactors and Normal Individuals 

to Stimulation with Agonists: Isoproterenol, 

Prostaglandin E

1 , and TDI 

138 
E 

ci 

u 

1600 · 

1500. 

1400. 

1300 

1200 

1100 · 

1000 · 

900, 

800. 

700· 

600, 

500 

400, 

300, 

200 

100. 

0 

TMI/HSA· HSA 

METHOD 

• • • 

-------- • •• 

• • 

•n ··1··· , .. 'ii~• .... .~t:. 

REACTOflS CONTROLS 

RAST INDEX 

• 

• 

• 

• -------- •••• • •• • •• • • • •••••••• • •• •• • •• •• • 

•• ••••••• 

• •••• • • a• 

REACTORS CONTROLS 

Figure 10 

Radioallergosorbent Tests with p-tolyl Monoisocyanate 

of Sera from TDI Reactors and Controls 

139 

9 

8 

:::0 ~ 7 l> 

CJ) 

-i 

6 

::, 

ci 

a, 

5 )( 

4 

3 

2 

0 
I i i ! 1mm G~ 

: ! I : ·nn-;w-,r, 

IO" ~- 11 

i i to· lO" ~. ·c 

II !I ' I I 

ji ii 

I!, ! I 

' 

·11 :i 

i. 

:111 

ii I 

; , I I I 

i ! I : 

' ra ' I I 

I : 

' 

~ ::::, a: 

~ 0 

I-

-

' I I 

' 

TO\l·:W'cl'cl 

80' ~· ., to· IO'U' 0 

a: z 

£L 0 

2 

a:: 

I 

l r I I! I 

I II!: i I I d n 

~ <( 

0 1'J a: a: 8 <( 

~ 

a: 0 

' : 

11 

I! 

Ii I 

:. I' 

I : . ' 11 1 

1:,: ' I • 

! 

'·' 6 I. I I ! : : I ; i, rlli . ' 

I' I II i!!i I,' I . ~ 

'! I '' I,, 11 

' !ii 1 

I' I '. I' I• I 

I-

;rl 2 

0 0 

it ff >- If I I :fll

lli I 

I I . 1 I I I. fl I., I 

!,o· 

TO'J.·;w·c1·c1 

' . J ' I ~· ' t)(' . 10·: soo· 0 

; :"i, ,l.4i iJ, I I l. . ~ - J. 

t I i 

-- ~ .. . 

' i I 

:.: ,11 ....... I 

I ' 1: 1 I I ; 111 I Ill ii 9 ' r 1· I! ,, 

I' I , · . I; I , 111 ! 11 i i 

: ; ii ' ·1 :1 1 i I i I 

i 

1 1 i 1 .i! I: ·1111 i 

: i ! : ,ii ' .I s 

,, i ,'' , ' TQ'J.·'W'cl'ol I I , ' 

!,'. ~·:I; I to:

li ! 1 

ILo·; soo· • 

l.llll Ul.i:l lll lllill 111111n11 II 
CONCURRENT I MPINGER 

AND MONITOR TOI LEVELS 

(field) 

.035 

• . 030 

~ • ....... 

t5 • ~ . 025 

~ r = .81 

• 

'- . 020 

~ 

~,,; 

.015 },e~ 

~ o\ 

.~e ... . 010 • ,, ....... 

~ .005 

o~----...._-.---,,-------.---.------.----, 

0 .005 .010 .015 .020 .025 .030 .035 

TD I , PPM (Monitor) 

Figure 12 

141 
-i 

1-rj ~ .... rr, I-" ()Q .. ~ C N 11 

(1) z 

w 

I-' ~ rr, 

rr, 

~ 

(/) 

8- 13-73 

9- I0-73 

10- 15-73 

11 - 19-73 

12-24-73 

I - 28-74 

TOI CONCENTRATION IN PPM 

0 0 

N 

·-=~~Ii;:=~-

;;_:~~ 

- =-• 

0 

vi 

------------· 

----.... 

0 

.:. 

3- 4-74 ...-----

4- 8-74 

5- 13-74 

6- 17-74 

7- 22-74 

8-26-74 

9-30-74 

11- 4-74 

----~-...z~---:.~::::.~ 

~ ~--=---------.,_ . ''I' .... __ .,..,,.. ... -... 12- 9-74 .:. ___ ..,.. 

I - 13-75 

2- 17-75 II 

3-24-75 

4-28-75 

6- 2-75 

7- 7-75 
11 

9 

~ 7 

(l) 

~ 5 

3 

7 

5 

3 

5 

3 

TOI PLANT 

HISTOGRAM OF WEEKLY TWA 

Nov 73 to Sep 74 

Mean = 0.0153 ppm 

Std, Dev.= 0.0111 

Sep 74 to Mar 75 

Mean = 0.0223 ppm 

Std. Dev.= 0.0090 

Mar 75 to June 75 

Mean = 0.0 I 02 ppm 

Std. Dev.= 0.0056 

l() l() l() l() l() l() 

~ l() l() l() l() 

C) '3- ~ '3- 0) '3- ~ 0) ~ 0) 

C) C) ' ' (\J ~ ~ '3- '3-

~ ~ ~ C) C) - ~ ~ ~ ~ 

ppm 

Figure 14 

143 
TOI DRUMMING BUILDING 

HISTOGRAM OF WEEKLY TWA 

19 11/5/73 to 8/26/74 

17 Mean = 0.0078 ppm 

15 Std. Dev. = 0.0096 

13 

11 

9 

7 

~ 5 

Q.) 

~ 

' C) 

i..... 

Q.) Mean = 0.0066 ppm ~ Std. Dev.= 0.0038 § 

< 

7 3/3/75 to 7/21/75 

5 Mean = 0.0110 ppm 

3 Std, Dev. = 0.0070 

le) le) 

~ le) 

~ le) 

~ le) le) le) le) 

B ~ ~ ~ ~ O') ~ O') 

C) C) ....... ....... 

~ ~ h') 

~ "" ~ C) ~ C) ~ C) C) ~ C) 

ppm 

Figure 15 

144 
TYPICAL RECORDER PRltfTOUT 

FROM TOI PERSONAL MONITOR 

T.D.I -- DATAGRAM'• 

"' 0 ----:.c11- -f "C' ... 

I: ~ 3· .oe n 

Ei "' . ..,. • C: 

ii -< .05 1----:18-

~ "' ·-,- 0 

r 

.d. II :, 

er • ~18- 1 

I? w ~J ... i~ - ,.. -~-::'4- r ; ;- 3. .03 "' -o~ 

- II ~ a f~ ... - iil -·- g ~= -- --~ ~~ . --n -... - .. =: 0 -:12~ • :, 0 .. ~ I -~ --~ ~ -- . Z -0- n _.,,_ ... -"'-- .. 02 z . 2 ~·~10- -<-'-- --· r--.--

i 0 " > -:a- n ... _ =~~!- . I 

?; - -- 0 ' ::! z z 0 -z--

" z .;,-'- =~:;os== i .01 " .01 ic 

"' I - -l- -:.04-

·1 

" 6 

\ --,02- I J" 

r - I 

' " ,._J - - ~ 7 

2 3 " C 1 4 I I 1 

EI.Al'SED TIME- HRS 

• I OWIT NO. IICIII 4tOO ,-qo•u.a.A. MDA 8aENTW'IC INC. PAltll: llllDGI. L eooe8 U.S.A. 

Figure 16 

145 
Q) c~ C\J 

C a.>-- ~ 

CJ) )( 

0:: \ 0 o.Q w \ .c .~o 0 a.. \ (.) z 0: \ I 0 

\ I \ 0 \ I 

r- CJ) 

I C\J 

\ 0 0 

LL 0:: \ z 

0~ \ (0 

\ "- ....... 

0 .-I 

CJ) z \ Cl) 

\ 1-4 WO C\J ::, '° ..;t 

Cl) I() 00 ~ 

0~ \ 

u Tl ~ . ::) w \ E tn a.. \ CL 

~ \ v CL 

\ w \ (.) \ z \0 ro w 

0:: \ 

w 0 

LL \ 

0:: \ C\J 

w \ 

r- \ 

z \ 

\ 

\ 

\ 

\ 

0 I() 0 I() 00 

C\J Q Q 0 

Q Q 

( Dl1/pOa8 OOOL /apow) 

/0.J. JO wdd 1ua1011,1nb3 
TD I DATAGRAM 

.08--------------

.071-------------------1 

.061-------------------1 

.05--------------

.04~-----------------t 

.03--------------

" .005 

~ o....._---~~~--~~------ 10 20 30 40 50 60 70 80 

Time ( Minutes) 

Time Scale Expanded 

Figure 18 

147 
EFFECT OF TEMPERATURE 

ON MODEL 7000 TDI MONITOR 

1.6 ................ 

~~ 1.4 

~t 1.2 ~ C)I 1.0 

~ 0.8 r,;::: •:,..... 

-....:: ~ t:s 

0.6 "'6 ~ 

~~ 

• 

• e_ No Temperature - - - - - - -.-- -.-- - - - - Effect Line 

I 

• 

0.4 

-~ 

0.2 cg ' 

0.0 

-10° oo 10° 20° 30° 

Temperature °C 

Figure 19 

148 
ON 

1.8 .............. 

~~ 1.6 

~ ~ 

~ 1.4 

~I 1.2 

~ ~ 1.0 ....... ~ 

~ {.) 

(:) ~ 0.8 ~~ 

-~ 

0.6 

~ 

~ 0.4 

0.2 

o.ol l 

0 

EFFECT OF HUMIDITY 

MODEL 7000 TOI MONITOR 

20 40 

No Humidity - - - - - - - - - Effect Line 

60 80 100 

0

/o Relative Humidity at 22.5° C 

Figure 20 

149 
DISTANCE BETWEEN SELECTED JOBS 

40 E-OPERATOR 

30 DRUMMING 

20 

10 

0 . 

0., 

"') 40 ~ 

...... FOREMAN 

......: ........ TOI ,, 

t:::: 30 

•• (l) s;, 

Cb ~ 20 

<I). 

~ c3' 

~ :::s 

10 C') 

Cb ."> ,, ~ 0 . 

40 BUG POND ~ 

30 OPERATOR 

20 

10 

0 

I 2 3 4 5 6 7 8 

Category of Log (TWA) 

Figure -21 

150 
,, 

DISTANCE BETWEEN SELECTED JOBS 

40 

30 

20 

A-OPERATOR 

TOI 

10 

oL.i~VAiV&!WM~-------------

40 

' ~ 30 

0-0PERATOR 

PHOSGENE 

~ 20 

"-~ 10 

0 

40 

30 

20 

FOREMAN 

TOI 

10 

OL......K2'Boll~~'LμU.~rpfU..fLK,ir,c.A--

I 2 345 67 8 

-Category of Log ( TWA ) 

Figure 22 

151 

,, 
REPRINTS INCLUDED IN NIOSH FINAL REPORT - 10/12/79 

1. Respiratory Effects in Toluene Diisocyanate Manufacture: A Multidisciplinary 

Approach - Weill, Salvaggio, Neilson, Butcher, Ziskind 

2. Longitudinal Study of Workers Employed in the Manufacture of TolueneDiisocyanate - Butcher, Jones, O'Neil, Glindmeyer, Diem, Dharmarajan, 

Weill, Salvaggio 

3. Environmental characterization of toluene diisocyanate (TD!) in a 

manufacturing plant - Dharmarajan, Weill, Self 

4. Physical state of airborne p.p' diphenylmethane diisocyanate (MDI) 

and its measurement - Dharmarajan and Weill 

5. Occupational Exposures to Methylene Bisphenylisocyanate (MDI): 

Gaseous or Aerosol - Dharmarajan 

6. Analysis of Toluene Diisocyanate (TDI) and p.p'-Diphenylmethane 

Diisocyanate (MDI) in Air - Dharmarajan 

7. The in vitro effect of toluene diisocyanate on lymphocyte cyclic 

adenosine monophosphate production by isoproterenol, prostaglandin, 

and histamine - Davies, Butcher, O'Neil, Salvaggio 

8. Occupational asthma caused by low molecular weight chemical agents -

Davies, Butcher, Salvaggio 

9. Occupational Asthma - Karr, Davies, Butcher, Lehrer, Wilson, Dharmarajan, 

Salvaggio 

10. Toluene diisocyanate (TD!) pulmonary disease: Innnunologic and inhalation 

challenge studies - Butcher, Salvaggio, Weill, Zisk.ind 

11. Toluene diisocyanate Pulmonary Disease: Immunopharmacologic and 

Mecholyl Challenge Studies - Butcher, Salvaggio, O'Neil, Weill, Garg 

12. Inhalation challenge and pharmacologic studies of toluene diisocyanate 

(TD!) - sensitive workers -- Butcher, Karr, O'Neil, Wilson, Dharmarajan, 

Salvaggio, Weill 

13. Inhalation challenge testing with. toluene diisocyanate CI'DI} -

Butcher 

14. Radioallergosorbent Testing (RAST} of TDI Reactive Individuals using 

p-Tolyl Isocyanate (TMI) Antigen - Butcher, O'Neil, Salvaggio 

15. A new method for the generation of standard atmospheres of organo 

isocyanates - Dharmarajan, Rando. 

152 o U.&. CIOYEIINMEIIT ""NllNG OFFICE: 1•1 - 757-074/3603 

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PUBLIC HEAL TH SERVICE 

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NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEAL TH 

ROBERT A. TAFT LABORATORIES 

4676 COLUMBIA PARKWAY, CINCINNATI, OHIO 45226 

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