Risk Analysis of the NJH Data Set from the Beryllium Machining Facility in Cullman, Alabama  -  CBD and Sensitization

1.  Introduction/overview
	OSHA's risk assessment for beryllium sensitization and Chronic Beryllium Disease (CBD) was developed to provide the Agency with information pertinent to the beryllium rulemaking, including:
 A characterization of the risks of beryllium sensitization and CBD for workers exposed to airborne beryllium at the level of the preceding time-weighted average permissible exposure limit (TWA PEL); and
 A characterization of the reduction in risk that lowering the TWA PEL would be likely to achieve.
The risk assessment for the beryllium rule incorporates both qualitative and quantitative analyses to characterize these risks, including (1) a review of the published literature on recent beryllium exposure control programs, and (2) analyses of a data set provided by National Jewish Health (NJH) on a population of workers employed at a beryllium machining plant in Cullman, Alabama.  In section VI of the preamble, OSHA presents its final review of the published literature as well as its final analyses of the NJH data set.
      This document supplements the material presented in section VI regarding OSHA's final prevalence and statistical analyses of the NJH data set.  It contains details regarding the data set itself and OSHA's preliminary and final analyses of it.  OSHA's statistical analysis was updated in response to comments received on the preliminary risk assessment from Dr. Kenny Crump and Ms. Deborah Proctor (Document ID 1660) and NIOSH (Document ID 1725), which are addressed in this document as well.  A preliminary version of OSHA's analyses of the NJH data set was presented in the NPRM and a technical document (Risk Analysis of a Worker Population at a Beryllium Machining Facility, OSHA, 2014, Document ID 1589).
2.  Background on the Cullman, AL machining plant
	NJH researchers, with consent and information provided by the facility, compiled a data set containing employee work histories, medical diagnoses, and air sampling results, and provided it to OSHA for analysis.  OSHA's contractor, Eastern Research Group (ERG), gathered additional information: for example, ERG conducted surveys of the Cullman plant (ERG, 2003, Document ID 1876; ERG, 2004a (1877)) and also collected published articles of independent investigations conducted at the plant (Kelleher et al., 2001, Document ID 1363; Madl et al., 2007 (1056); Martyny et al., 2000 (1053); and Newman et al., 2001 (1354)).
	The Cullman, AL, machining plant is a fabricator of precision machined and processed materials, including beryllium and its alloys, titanium, aluminum, quartz, and glass. The company was founded in Michigan in 1947 and began working with beryllium in the mid-1950s (Cullman Chamber of Commerce, 2003, Document ID OSHA-H005B-2006-0898-0631).  The available information indicates the company moved its operations to Alabama and operated at least two facilities in Cullman, Alabama (Cullman Chamber of Commerce, 2003, Document ID 0631; OSHA, 2014 (1589)).  The current facility has been in operation since 1969 (Martyny et al., 2000, Document ID 1053; Kelleher et al., 2001 (1363); Madl et al., 2007 (1056)).   Machining operations in the old Cullman facility were consolidated into the company's current Cullman location in 1974 (see OSHA, 2014, Document ID 1589).
	Production operations at the plant include receipt and inspection of materials, machining and polishing, chemical finishing (acid etching), and inspection and quality assurance.  Machining operations include milling (manual and CNC milling), lathe work, lapping, grinding, deburring (grinding with a small hand-operated tool (Martyny et al., 2000, Document ID 1053)), and electrical discharge machining (EDM).  Management and administrative personnel include two groups: those primarily working in the front offices (front administration) and those primarily working on the shop floor (shop management).  Most of the plant's beryllium operations involve machining beryllium metal and high beryllium content composite materials (beryllium metal/beryllium oxide metal composites called E-Metal or E-Material), with occasional machining of beryllium oxide/metal matrix (such as AlBeMet, aluminum beryllium matrix) and beryllium-containing alloys (Madl et al. 2007, Document ID 1056).

Exposure Conditions Over Time
	Plant conditions over time and source material for this information are summarized in Table 1.  Prior to 1995, exposure controls for machining operations primarily included a low volume/high velocity (LVHV) central exhaust system with operator adjusted exhaust pickups and wet machining methods.  Madl et al. reported that the company prioritized use of engineering and administrative controls to limit workers' beryllium exposures rather than respiratory protection and other PPE (2007, Document ID 1056).  Similarly, OSHA found inconsistent use of work uniforms, gloves, and respiratory protection (ERG, 2004a, Document ID 1877).
	Prior to the diagnosis of a case of CBD in 1995, the company's exposure sampling and control strategies focused on maintaining compliance with OSHA's preceding TWA PEL of 2 μg/m[3].  After the diagnosis, the facility established an in-house target exposure level of 0.2 μg/m[3], installed change/locker rooms for workers entering the production facility (one for production workers and one for office/administrative workers), eliminated pressurized air hoses and discouraged dry sweeping to reduce re-entrainment of beryllium particles in the air, initiated biennial medical surveillance using the Beryllium Lymphocyte Proliferation Test (BeLPT), and implemented annual beryllium hazard awareness training.
	In 1996, the company instituted a formal policy requiring the use of work uniforms and dedicated work shoes for production workers, eliminated dry sweeping in all departments, and purchased high-efficiency particulate air (HEPA) filter vacuum cleaners for workplace cleanup and decontamination.  The company also initiated major engineering changes that year, including the purchase of a new local exhaust ventilation (LEV) system to exhaust machining operations producing finer particles (i.e., dust as opposed to metal chips).  The facility also began installing mist eliminators for each machine.  Dry machining operations producing chips were exhausted using the existing LVHV exhaust system (ERG, 2004a, Document ID 1877).  In the course of making the ventilation system changes, old ductwork and baghouses were dismantled and new ductwork and air-cleaning devices were installed.  The company also installed Plexiglas enclosures on machining operations, including lapping, deburring, grinding, EDM, and tool and die operations, between 1996 and 1997.  In 1998, LEV was installed in EDM and modified in the lap, deburr, and grind departments.
	As shown in Table 1, most exposure controls were in place by 2000.  In 2003, the company replaced the LVHV ductwork in the milling and lathe departments (ERG, 2004a, Document ID 1877).  Over time, the facility has built enclosures for operations that consistently produce exposures greater than 0.2 μg/m[3].  In 2004, two surface grinders were fully enclosed and ventilated (ERG, 2004a, Document ID 1877).  That year, the plant also opened a new 20,000-square-foot manufacturing facility to produce the unpolished beryllium mirror segments for the James Webb Space Telescope, the nation's next-generation space telescope and successor to the Hubble.  The new facility houses advanced computer-aided manufacturing and metrology equipment with state-of-the-art ventilation controls, full equipment enclosures, and smooth, easily cleanable surfaces (Marcial and Martyny, 2007, Document ID 1121).

            Table 1:  Exposure Conditions at the Cullman, AL Plant

Events
                                     Dates
References

Workplace practices reported to be relatively stable. Exposure control strategy included wet methods and LVHV exhaust system (i.e., Spencer system with baghouses). Inconsistent use of work uniforms by employees.

                                 Prior to 1995

ERG, 2004a;
Kelleher et al., 2001; OSHA, 2014, Document ID 1589

Identification of one worker with CBD (index case).

                                     1995

Newman et al., 2001

Established in-house target exposure level of 0.2 μg/m[3] (8-hour TWA).

                                1995 - Present

Marcial and Martyny, 2007

Installed change/locker room for production workers at rear entrance to facility with a clean side and a dirty side. Installed change room for office/administrative workers entering plant; lab coats and shoe covers required to enter machining area.

                                     1995

OSHA, 2014, Document ID 1589

Initiated practice of purchasing new machines with enclosures (i.e., when old, open equipment needs to be replaced, it is replaced with new, enclosed equipment).

                                     1995

Marcial and Martyny, 2007

Initiated annual beryllium hazard awareness training for workers.

                                     1995

Marcial and Martyny, 2007

Removed pressurized air hoses used for blowing beryllium dust off machines and discouraged dry sweeping.

                                     1995

OSHA, 2014, Document ID 1589

Eliminated dry sweeping in all departments. Purchased approximately 10 high efficiency particulate air filter (HEPA) vacuums for workplace cleanup and decontamination.

                                     1996

Madl et al., 2007;
Newman et al., 2001; OSHA, 2014, Document ID 1589

Installed 5 Donaldson Torit LEV systems for dust/fume/mist-producing operations. Departments exhausted by Donaldson system include cutter grind (tool and die), E-cell, EDM, flow lines, grind, lapping, and optics. Some Spencer baghouses and ductwork eliminated (old Spencer ductwork dismantled; new Donaldson ductwork installed).

                                     1996

OSHA, 2014, Document ID 1589

Began installing Plexiglas enclosures on machining operations; started with deburring.

                                     1996

Kelleher et al., 2001; OSHA, 2014, Document ID 1589

Installed enclosures on lapping, deburring, grinding, EDM, and tool and die operations.

                                  1996 - 1997

Madl et al., 2007

Installed mist eliminators on some CNC milling, EDM, grinding, lapping, and cutter grinding (tool and die) processes.

[Note: Mist eliminators not used for machining operations producing chips. Some machines exhausted to large outdoor mist eliminators that handle multiple pieces of equipment; other machines vented to individual mist eliminators located inside the machine shop.]

                                  1996 - 1997

Madl et al., 2007;
OSHA, 2014, Document ID 1589

Around 1996, the company implemented a formal policy requiring mandatory use of company uniforms and dedicated work shoes. Policy has been included in employees' manual.

[Note: Employee uniforms have been available at least since 1973 (NIOSH, 1973).]

                                  1996 - 1997

Kelleher et al., 2001;
Madl et al., 2007; OSHA, 2014, Document ID 1589

Workers must wash their hands, forearms, and face before breaks/lunch and after the shift. Personal hygiene is included with employee training.

                              At least since 1996

Marcial and Martyny, 2007;
OSHA, 2014, Document ID 1589

Installed LEV in EDM and updated it in the lap, deburr, and grind departments.

                                     1998

Kelleher et al, 2001;
Madl et al, 2007

Replaced LEV ductwork in the mill and lathe departments.

                                     2003

ERG, 2004a

Wearing long sleeves becomes mandatory.

[Note: Initially workers wore disposable sleeves, now workers wear long sleeve shop coats with elastic cuffs. Glove use not mandatory; however, wearing gloves is emphasized in training and workers are encouraged to wear gloves whenever possible or feasible.]

                                  2004 - 2005

Marcial and Martyny, 2007; OSHA, 2014, Document ID 1589

All machines have exhaust ventilation and about 65% of machines are also enclosed with either partial or full enclosures to control the escape of machining coolant.

                                     2004

ERG, 2004a;
OSHA, 2014, Document ID 1589

Installed full LEV enclosures on two surface grinder operations. Surface grinder operator exposure reportedly reduced from an average of 1.6 μg/m[3] to 0.08 μg/m[3] (8-hr TWAs).

                                     2004

ERG, 2004a

Description of the Cullman, AL, Data Provided by NJH
      NJH researchers compiled employee work histories, medical diagnoses, and air sampling results for the machining plant, and provided these data to OSHA.
Work History
      The work-history data set contains records for 348 workers and includes fields for each worker's job(s), start date, time spent at each job, and percentage of work time spent in each job for workers who held two or more jobs concurrently.
	Machining job titles and departments in the NJH data set include the following: cathode (cath), deburr, E-Cell, EDM, flow lines (flow), gas bearings (gas), glass (non-beryllium machining), grind, HRG cell (non-beryllium machining), James Webb Space Telescope (JWST), lap, lathe, mill, optics, QRoom, specialty cell worker (spec), and tool (non-beryllium machining).  The job title "tool" can also be known as tooling, tool making, tool grinding, tool and die, and cutter grinding (or cgrinding); it refers to workers that repair, maintain, fabricate, and modify machine-cutting tools. Workers can be exposed to beryllium when they perform servicing activities on cutting tools that are contaminated with or contain beryllium.  Non-machining job titles or departments include (but are not limited to) administrator, assembler, custodian, chemical finisher, engineer, estimator, health and safety, ion milling, inspector, maintenance, manager, numerical control (NC) programmer/manufacture programming, product control/inventory control, sales, shipper, and shop management (shop floor).  Table 2 summarizes available information regarding job title descriptions of interest.

             Table 2. Beryllium Metal Machining Plant -- Job Titles

                                    Job ID
                                Job Title Code
                                   Comments
                                      11
Lathe
Machining. A machine tool for shaping metal or wood; the workpiece (block of material) turns or spins about a horizontal axis against a fixed single-edge cutting tool. The lathe can perform turning, facing, threading, drilling, and other operations.
                                      12
Lapping
Machining. An abrasive machining operation where two surfaces are rubbed together with an abrasive between them to remove unwanted material. Lapping may be done by hand or by machine.
                                      13
Deburring
Machining. Removing burrs from manufactured parts. A burr is a thin ridge or area of roughness produced by cutting or shaping metal. Deburring may be done by hand with hand-deburring tools or with automated deburring machines.
                                      14
Grinding
Machining. An abrasive machining process to remove material from the workpiece. A grinding machine is a machine tool for producing very fine finishes, making very light cuts, or high precision forms using an abrasive wheel as the cutting device. The simplest grinder is a bench grinder or a hand-held angle grinder for deburring parts or cutting metal with a zip-disc.
                                      15
Milling
Machining. Milling is the complex shaping of parts (metal or possibly other materials) by removing unneeded material to form the final shape. Milling is done on a milling machine with a rotating multi-edge cutting tool; the workpiece is fixed. Milling machines may be operated manually or under computer numerical control (CNC) and can perform many complex operations such as slot cutting, planing, drilling and threading, rabetting, routing, etc.
                                      16
NC Programmer
Production support/engineering. Numerical control (NC) programming. Providing manufacturing programming support for numerically controlled machine tools. Job activities could include analyzing engineering drawings for parts, defining and creating programs for machining work centers (e.g., selecting proper cutter and program routines for efficient computer calculation of dimensional and machining requirements for parts), interfacing with shop personnel, and other machine shop activities.
                                      17
Optics Department
Machining beryllium. Primarily polishing and lapping small parts; some hand operations. [Note: The ERG Site 4 and 9 survey reports indicate that the optics department specializes in making high tolerance mirrors (nickel on a beryllium substrate) and that beryllium parts are also lapped (machined) there.]
                                      18
HRG Cell
Non-beryllium (glass/quartz) machining. HRG likely refers to hemispherical resonator gyroscope. The James Webb Space Telescope will have HRGs to sense the orientation of the telescope. HRGs are constructed with three pieces of machined quartz. [Note: During the ERG Site 4 survey, beryllium wipe samples were collected in the quartz work area which does not use beryllium but is adjacent to areas that process beryllium-containing parts.]
                                      19
Tooling
Non-beryllium machining/production support/toolmaking. Tooling refers to workers that repair, maintain, fabricate, and modify machine-cutting tools. Per Kelleher et al. (2001) tool grinders do not machine beryllium.
                                      20
Clean Room
Non-machining. Refers to an area where precise inspection operations are performed.
                                      21
Assembly
Production support/mechanical assembly. Refers to mechanical assembly of beryllium and non-beryllium parts. Can involve tapping holes and inserting pins. Assembler is a major non-machinist job title per Kelleher et al. (2001).
                                      22
Inspection
Production support/inspection. Inspector is a major non-machinist job title per Kelleher et al. (2001).
                                      23
EDM
Machining/electrical discharge machining (EDM). Machining electrically conductive materials by using precisely controlled sparks that occur between an electrode (cutting tool) and a workpiece in the presence of a dielectric fluid. EDM is a thermal process; material is removed by heat. The material between the electrode and workpiece is heated to the point where the material vaporizes.
                                      24
Chemical Finishing
Production support/chemical finishing or acid etching. Chemical finisher is a major non-machinist job title per Kelleher et al. (2001).
                                      25
Production Control
Non-machining per Madl et al. (2007); management/administrative. Manager and administrator are major non-machinist job titles per Kelleher et al. (2001). Production control typically refers to the systematic planning, coordinating, and directing of all manufacturing activities and influences to insure having products made on time, of adequate quality, and at reasonable cost.
                                      26
Maintenance
Non-mailing per Madl et al. (2007). Production support per Kelleher et al. (2001).
                                      27
Estimating
Non-machining. Production support/engineering. This job title code refers to production estimator. Estimators analyze blueprints, specifications, proposals, and other documentation to prepare time, cost, and labor estimates for products, projects, or services, applying knowledge of specialized methodologies, techniques, principles, or processes. Consults with clients, vendors, or other individuals to discuss and formulate estimates and resolve issues. May specialize according to the particular service performed, type of product manufactured, or phase of work involved.
                                      28
Engineering
Non-machining. Production support per Kelleher et al. (2001).
                                      29
Manufacture Programming
Production support/engineering. This may be referring to NC programming or something similar.
                                      30
Shop Management
Non-machining per Kelleher et al. (2001). Refers to management and administrative personnel that predominantly work on the shop floor (shop management).
                                      31
Salaried Sales
Non-machining per Kelleher et al. (2001). Production support/sales and administration.
                                      32
Front Administration
Non-machining per Kelleher et al. (2001) and Madl et al. (2007). Refers to management and administrative personnel that predominantly work in the front offices.
                                      33
Flow line
Machining. Primarily machine aluminum spindles; occasionally (infrequently) machine beryllium. The lean manufacturing line where a part is processed along an assembly line. [Note: Specialty cell workers ("Spec") are now categorized under flow lines. During the ERG Site 4 survey, a beryllium wipe sample was collected in the flow line area which is near the grind department and the quartz work area.
                                      34
Health and Safety Personnel
Non-machining. Kelleher et al. (2001) included health and safety with shop management.
                                      35
Specialty Cell/E-Cell/Cathode Cell
Machining. Specialty cell refers primarily to aluminum machining; glass, quartz, and beryllium are also machined in specialty cell. E-cell refers to E-cell lapping department or E-60 area. Cathode refers to cathode grinding (adjacent to lathes).
                                      36
Contract Worker
Not enough information is provided to determine if this job title code pertains to machining.
                                      37
Gas Bearing
Machining per Madl et al. (2007). Per the ERG Site 4 and Site 9 survey reports, the gas bearings department uses beryllium.
                                      38
Glass
Non-beryllium machining. Machining (e.g., lapping, grinding, milling) optical glasses (infrared lenses).
                                      55
Laid Off
May have referred to both machinists and non-machinists. During 1999/2000, the plant experienced a downturn in business and laid off 60 to 70 workers.
Sources: Kelleher et al. (2001); Madl et al. (2007); OSHA, 2014, Document ID 1589
Screening results
      Plant-wide screening for beryllium sensitization using the BeLPT began in May 1995 and was conducted biannually for all employees (Newman et al., 2001, Document ID 1354).  Employees hired or rehired after the initial screening were tested within three months of hire and biannually thereafter.  Thus, employees working at the plant in May 1995 were eligible for follow-up testing in 1997, 1999, 2001, and so on, until they left employment or were found to be sensitized.  Employees receiving their first test in 1996 were eligible for follow-up testing in 1998, 2000, and so on.  In his 2001 publication on the surveillance program, Dr. Lee Newman reported 100 percent participation in follow-up testing among eligible employees (Newman et al., 2001, Document ID 1354).
     	The data set of sensitization screening and CBD diagnoses contains records for 363 workers and includes fields for birth year, year of hire, smoking status, and type of diagnosis.  All 348 workers included in the work-history data set are also represented in the diagnosis data set.  Of the 15 remaining workers in the diagnosis data set, 10 were initially hired in 2004 or 2005, three were first hired between 1997 and 2000, and the initial hire year was not given for two workers.  Seven workers are reported as sensitized only, 16 workers are listed as sensitized and diagnosed with CBD only, and three workers are shown as first sensitized and then diagnosed with CBD.  None of the workers who are absent from the work-history data set are reported as CBD or sensitization cases.
Industrial Hygiene Sampling Data
      The NJH data set includes industrial hygiene air sampling results for the beryllium metal machining plant from 1980 to 2005.  The exposure data set includes air samples collected by the plant (1980 to 1984 and 1995 to 2005) and NJH (June 1996 to February 1997, and September 1999).
      A total of 5,082 records comprise the results for 4,370 personal breathing zone samples and 712 area samples.  Sampling data include the sample date, flow rate, sample time, sample volume, sampler type (filter or impactor), sample type (breathing zone or area), and exposure value (in micrograms per cubic meter (μg/m[3])).  Sample times are provided for 2,557 of the personal breathing zone samples.  Sampling times for the plant-collected data are available for 94.8 percent of samples through 2003.  All samples for 2004 and 2005 are full-shift samples (approximately eight hours in duration) (OSHA, 2014, Document ID 1589).  All results in the database represent beryllium concentrations that are based on the actual sampling times (i.e., none of the results have been time-weighted for eight hours).  Table 3 below shows the total number of personal breathing zone samples collected for each process.
                    Table 3. Samples collected by Job Title

Process Name
                             Number of PBZ Samples
Admin
                                      171
Assy
                                      10
Cath
                                      30
Cgrind
                                      149
Chem
                                      212
Deburr
                                      156
Ecell
                                      118
Edm
                                      127
Eng
                                      258
Flow
                                      184
Gas
                                      186
Glass
                                      65
Grind
                                      148
Health and Safety
                                       6
Insp
                                      337
Jwst
                                      60
Lap
                                      246
Lathe
                                      386
Maint
                                      147
Mill
                                      926
Msupp
                                      219
Optics
                                      89
Pcic
                                      86
Qroom
                                       3
Shop
                                       4
Spec
                                      46
Tool
                                       1

All processes
                                     4,370

Construction of Job-Exposure Matrix
	Using the industrial hygiene data set described above, ERG developed a job-exposure matrix (JEM) for the beryllium machining facility.  Of the samples in the database for which sample times were recorded, 97.9 percent (2,503 out of 2,557) were personal breathing zone samples with sample times greater than or equal to 400 minutes.  No adjustments were made for sampling time, except in the case of four samples for the "maintenance" process for 1995.  These results show relatively high values and exceptionally short sample times.  The four 1995 maintenance samples were adjusted for an eight-hour sampling time assuming that the maintenance workers received no further beryllium exposure over the rest of their work shift.
	After reviewing the sample statistics for individual years for different groupings, ERG evaluated the following year groupings to construct the exposure history of workers contained in the work-history database:
Primary Machining Jobs (see Table 4) - 1980 to 1995; 1996 to 1997; 1998 to 1999; 2000 to 2003
Other Jobs (see Table 5) - 1980 to 2003
	The time periods selected for primary machining jobs correspond to stages in the plant's approach to beryllium exposure control described in the previous section.  The first period of exposure sampling, 1980 to 1995, represents a period of relatively minimal control prior to the 1995 discovery of a case of CBD among the plant's workers.  In 1996 and 1997, the company began installing major engineering controls.  By 1999, many such engineering controls had been installed, and exposures were generally lower than in previous periods.  The plant completed installation of most exposure controls by 2000, and exposures were very low throughout the plant in the time period from 2000 to 2005 (mean sample values for most jobs < 0.15 μg/m[3]).  Tables 4 and 5 below present mean exposure values for machining and non-machining job categories using all samples in the data set, by time period.

         Table 4. Exposure Values for Machining Job Titles (μg/m[3])

                                   Job Title
                                  1980 - 1995
                                  1996 - 1997
                                  1998 - 1999
                                  2000 - 2003

                                    samples
                                     mean
                                    samples
                                     mean
                                    samples
                                     mean
                                    samples
                                     mean
Deburring
                                                                             27
                                                                           1.17
                                                                             20
                                                                           3.30
                                                                              0
NA
                                                                             67
                                                                           0.16
Electrical Discharge Machining
                                                                              2
                                                                           0.06
                                                                              2
                                                                           1.32
                                                                             16
                                                                           0.08
                                                                             63
                                                                           0.12
Grinding
                                                                             13
                                                                           8.48
                                                                              6
                                                                           0.49
                                                                             15
                                                                           0.24
                                                                             68
                                                                           0.15
Lapping
                                                                              9
                                                                           0.15
                                                                             16
                                                                           0.24
                                                                             42
                                                                           0.21
                                                                            103
                                                                           0.16
Lathe
                                                                             19
                                                                          13.99
                                                                              8
                                                                           1.13
                                                                             40
                                                                           0.17
                                                                            200
                                                                           0.10
Milling
                                                                             43
                                                                           0.64
                                                                             15
                                                                           0.23
                                                                             95
                                                                           0.17
                                                                            434
                                                                           0.12

       Table 5. Exposure Values for Non-Machining Job Titles (μg/m[3])

                                   Job Title
                                  1980 - 1995
                                  1996 - 1997
                                  1998 - 1999
                                2000  -  20033

                                    samples
                                     mean
                                    samples
                                     mean
                                    samples
                                     mean
                                    samples
                                     mean
Administration
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                             39
                                                                          0.052
                                                                             74
                                                                          0.061
Assembly
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              8
                                                                          0.136
                                                                              2
                                                                          0.051
Cathode
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              9
                                                                          0.156
Cgrind
                                                                              1
                                                                          0.120
                                                                              0
                                                                             NA
                                                                             14
                                                                          0.105
                                                                             76
                                                                          0.112
Chem
                                                                              0
                                                                             NA
                                                                              2
                                                                         12.731
                                                                             21
                                                                          0.277
                                                                             91
                                                                          0.152
Ecell
                                                                              0
                                                                             NA
                                                                             13
                                                                          1.873
                                                                              0
                                                                             NA
                                                                             26
                                                                          0.239
Engineering
                                                                              1
                                                                          0.065
                                                                              0
                                                                             NA
                                                                             49
                                                                          0.069
                                                                            125
                                                                          0.062
Flow Lines
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                            113
                                                                          0.083
Gas
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                            121
                                                                          0.058
Glass
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                             38
                                                                          0.068
Health and Safety
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              5
                                                                          0.076
Inspection
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                             32
                                                                          0.101
                                                                            150
                                                                          0.066
Maintenance
                                                                              4
                                                                          1.257
                                                                              1
                                                                          0.160
                                                                             16
                                                                          0.200
                                                                             70
                                                                          0.126
Msupp
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                             47
                                                                          0.094
                                                                             68
                                                                          0.081
Optics
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                             41
                                                                          0.090
PCIC
                                                                              1
                                                                          0.040
                                                                              0
                                                                             NA
                                                                             13
                                                                          0.071
                                                                             42
                                                                          0.083
Qroom
                                                                              1
                                                                          0.280
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              2
                                                                          0.130
Shop
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              4
                                                                          0.060
                                                                              0
                                                                             NA
Spec
                                                                              3
                                                                          0.247
                                                                              0
                                                                             NA
                                                                             24
                                                                          0.083
                                                                             19
                                                                          0.087
Tool
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              0
                                                                             NA
                                                                              1
                                                                          0.070

      Samples for the early time periods are notably sparse, particularly for some non-machining jobs.  This does not necessarily imply a weakness in exposure characterization for all jobs listed, as some jobs did not appear in workers' job histories during the earlier time periods.  For example, workers with the job "Flow Lines" or "Glass" only worked in those jobs from 2000 onward, and workers with the job "Gas Bearings" only worked in that job from 1999 onward.  However, this is not the case for all such jobs; for example, 26 workers in the data set worked in "Inspection" prior to the first sampling period for that job.
	ERG identified nine industrial hygiene samples that exceeded four times the 95[th] percentile value for the job title and time period in which they were collected.  These included samples in administration, chemical finishing, deburring, EDM, grinding, lapping, and lathe.  Upon further review of the data set and the processes in use at the plant, ERG judged that five of the nine outlier samples could plausibly have been accurate samples and should be retained in further calculations. ERG considered the remaining four outlier samples to be highly implausible, therefore likely to be sampling errors, and excluded them from further calculations.  The excluded sampling results are:
            Table 6. Erroneous Samples Excluded from the Analyses
                                     Year
                                     Date
                                    Process
                                    Sampler
                                  Sample Type
                                     Flow
                                     Time
                                    Volume
                                   μg/m[3]
                                                                           1997
                                                                      2/18/1997
CHEM
Filter
BZ

                                                                           2567
                                                                          24.93
                                                                           1996
                                                                      7/25/1996
DEBURR
Filter
BZ

                                                                           1326
                                                                          41.48
                                                                           1981
                                                                      8/12/1981
GRIND
Filter
BZ
1.88
                                                                            435
                                                                          817.8
                                                                          73.37
                                                                           1995
                                                                      5/10/1995
LATHE
Filter
BZ
2
                                                                             10

                                                                         250.00

                                     Year
                                     Date
                                    Process
                                    Sampler
                                  Sample Type
                                     Flow
                                     Time
                                    Volume
                                   μg/m[3]
                                                                           1997
                                                                      2/18/1997
CHEM
Filter
BZ

                                                                           2567
                                                                          24.93
                                                                           1996
                                                                      7/25/1996
DEBURR
Filter
BZ

                                                                           1326
                                                                          41.48
                                                                           1981
                                                                      8/12/1981
GRIND
Filter
BZ
1.88
                                                                            435
                                                                          817.8
                                                                          73.37
                                                                           1995
                                                                      5/10/1995
LATHE
Filter
BZ
2
                                                                             10

                                                                         250.00

				Following removal of these sampling results, the mean exposure sample values for these jobs were considerably reduced.  The final mean values were 0.53 for chemical finishing (1996-1997), 1.29 μg/m[3] for deburring (1996-1997), 3.07 for grinding (1980  -  1995), and 0.88 μg/m[3] for lathe (1980-1995), .
      Reviewing the revised sample statistics for individual years for different groupings, OSHA noted that exposures in the 1996 to 1997 period for some machining jobs were equivalent to, or even higher than, exposure levels recording during the 1980 to 1995 period.  During 1996 to 1997, major engineering controls were being installed, but exposure levels were not yet consistently reduced.  The Agency therefore used the following year groupings to construct the exposure history of workers contained in the database who performed primary machining jobs: 1980 to 1997; 1998 to 1999; and 2000 to 2003.  Exposure values from the time period 1980 to 1997 were used to estimate exposures for machining jobs prior to 1980.  In general, the use of data collected in later time periods to characterize exposures in earlier years may lead to some underestimation of early exposures.  Exposure estimates are most reliable for the post-2000 period and, to a lesser extent, the 1998 to 1999 period.
	Some jobs -- including N/C Programming, HRG Cell, Manufacture Programming, and Salaried Sales -- did not have associated sample values.  Few (< 10) workers in the data set were employed in these jobs.  Based on information on the nature of each job (see Table 2), ERG used samples collected in Engineering to characterize exposures in N/C Programming and Manufacture Programming; samples in Front Administration to characterize Salaried Sales; and samples in Optics to characterize HRG Cell (OSHA, 2014, Document ID 1589).

Development of Exposure Estimates for Workers
	The work-history data set included entries for 348 workers.  No job title was provided for eight workers in the data set, including three long-term workers (employed between 14 and 20 years), one shorter-term worker (5 years), and four workers with incomplete dates of employment.  None of these workers were found to be beryllium sensitized or diagnosed with CBD, and all eight workers were excluded from the analyses.  Seven of the workers in the data set were hired before 1969, the year reported in the published literature as the Cullman plant's first year of operations.  These workers, none of whom were found to be sensitized or diagnosed with CBD, were also excluded from the analysis.  An additional 14 workers were reported to have no exposure time.  These records may represent individuals who went through the hiring process but did not actually spend time at the plant, or they may reflect errors in the data set.  They were excluded from the analysis of sensitization and CBD prevalence in exposure quartiles described below, as it was not OSHA's intention to include unexposed individuals in the lowest quartile of exposure.  After these 29 exclusions, a total of 319 workers remained in the data set.
	The initial work-history data set includes values for the total time (including fractions of years) workers spent on each job recorded in the work-history database.  For confidentiality reasons, however, the exact initial start date (i.e., month and day) was not provided.  ERG imputed the amount of time in each year spent on a job by first assuming that an equal length of time was spent during the initial and final years of a job, and that full years were spent during the intervening years.  For example, for a work-history entry of 3 years in milling between 1997 and 2000, ERG assumed the worker was employed as a miller for 0.5 years in 1997, for 2 years in 1998 to 1999, and for 0.5 years in 2000.
	Cumulative exposure was calculated as , where ei is the arithmetic mean sample level for job (i) (in the appropriate time period) and ti is the time spent in job (i).  Cumulative exposure was divided by total length of employment to estimate each worker's lifetime-weighted (LTW) average exposure.  For the prevalence and logistic regression analyses discussed in the next section, exposures were estimated at the end of the reported work history for each worker who was not beryllium sensitized or diagnosed with CBD.  For workers with beryllium sensitization or CBD, exposure estimates excluded exposures following diagnosis.  For three workers who were identified as sensitized and later diagnosed with CBD, exposure estimates excluded exposures after they were found to be sensitized.  For the proportional hazards regression analyses, exposures were estimated at multiple times throughout a worker's follow-up.  This exposure construction is described in more detail below.
	Workers employed for long time periods in jobs with low-level exposures tend to have low average and cumulative exposures due to the way these measures are constructed (i.e., incorporating the worker's entire work history).  It has been suggested that higher-level exposures, such as those encountered in machining jobs, may be more relevant to development of sensitization or CBD than exposures experienced in administrative or other low-exposure work (Madl et al., 2007, Document ID 1056).  To explore this possibility, ERG constructed a third type of exposure estimate.  This measure reflects the exposure level associated with the highest-exposure job (HEJ) and the JEM time period during which the worker was employed in that job.  For example, a worker employed in deburring for one year in 1989 and in administration for 10 years from 1990 to 2000 would be assigned the exposure level associated with deburring in the time period 1980 to 1997.  This exposure estimate (HEJ), the cumulative exposure estimate, and the average exposure were used in a prevalence analysis and in statistical analyses.

3. Prevalence of Beryllium Sensitization and CBD

	In the database provided to OSHA, seven workers were reported as sensitized only, 16 workers were listed as sensitized and diagnosed with CBD upon initial clinical evaluation, and three workers were shown as first sensitized only and later diagnosed with CBD.  Tables 7 to 9 below present the prevalence of sensitization and CBD cases across several categories of TWA, cumulative, and HEJ exposure.  Exposure values were grouped by quartile.  Because all workers with CBD are also sensitized, the columns "Total" and "Total %" refer to all sensitized workers in the data set, including those with CBD and those not diagnosed with CBD.
 Table 7. Prevalence of Sensitization and CBD by LTW Average Exposure Quartile
                                               LTW Average Exposure  (μg/m[3])
                                                                     Group Size
                                                                Sensitized only
                                                                            CBD
                                                                          Total
                                                                        Total %
                                                                          CBD %
                                                                  0.0  -  0.080
                                                                             91
                                                                              1
                                                                              1
                                                                              2
                                                                           2.2%
                                                                           1.0%
                                                                   0.081 - 0.18
                                                                             73
                                                                              2
                                                                              4
                                                                              6
                                                                           8.2%
                                                                           5.5%
                                                                    0.19 - 0.51
                                                                             77
                                                                              0
                                                                              6
                                                                              6
                                                                           7.8%
                                                                           7.8%
                                                                    0.51 - 2.15
                                                                             78
                                                                              4
                                                                              8
                                                                             12
                                                                          15.4%
                                                                          10.3%
                                                                          Total
                                                                            319
                                                                              7
                                                                             19
                                                                             26
                                                                           8.2%
                                                                           6.0%

 Table 8. Prevalence of Sensitization and CBD by Cumulative Exposure Quartile
                                               Cumulative Exposure (μg/m3-yrs)
                                                                     Group Size
                                                                Sensitized only
                                                                            CBD
                                                                          Total
                                                                        Total %
                                                                          CBD %
                                                                  0.0  -  0.147
                                                                             81
                                                                              2
                                                                              2
                                                                              4
                                                                           4.9%
                                                                           2.5%
                                                                0.148  -  1.467
                                                                             79
                                                                              0
                                                                              2
                                                                              2
                                                                           2.5%
                                                                           2.5%
                                                                1.468  -  7.008
                                                                             79
                                                                              3
                                                                              8
                                                                             11
                                                                          13.9%
                                                                           8.0%
                                                                7.009  -  61.86
                                                                             80
                                                                              2
                                                                              7
                                                                              9
                                                                          11.3%
                                                                           8.8%
                                                                          Total
                                                                            319
                                                                              7
                                                                             19
                                                                             26
                                                                           8.2%
                                                                           6.0%

     Table 9. Prevalence of Sensitization and CBD by HEJ Exposure Quartile
                                                        HEJ Exposure (μg/m[3])
                                                                     Group Size
                                                                Sensitized only
                                                                            CBD
                                                                          Total
                                                                        Total %
                                                                          CBD %
                                                                    0.0 - 0.086
                                                                             86
                                                                              1
                                                                              0
                                                                              1
                                                                           1.2%
                                                                           0.0%
                                                                  0.091 - 0.214
                                                                             81
                                                                              1
                                                                              6
                                                                              7
                                                                           8.6%
                                                                           7.4%
                                                                  0.387 - 0.691
                                                                             76
                                                                              2
                                                                              9
                                                                             11
                                                                          14.5%
                                                                          11.8%
                                                                  0.954 - 2.213
                                                                             76
                                                                              3
                                                                              4
                                                                              7
                                                                           9.2%
                                                                           5.3%
                                                                          Total
                                                                            319
                                                                              7
                                                                             19
                                                                             26
                                                                           8.2%
                                                                           6.0%

	Table 7 shows increasing prevalence of total sensitization and CBD with increasing LTW average exposure.  The lowest prevalence of sensitization and CBD was observed among workers with LTW average exposure levels < 0.08 μg/m[3], where two sensitized workers were found (2.2%), including one case of CBD (1.0%).  The sensitized worker without CBD had worked at the facility as an inspector since 1972.  Because this job was believed to have very low exposures, it was not sampled prior to 1998.  Estimates of exposures in this job are based on data from 1998 to 2003.  It is possible that exposures earlier in this worker's employment history were higher than reflected in his estimated average exposure.  The worker diagnosed with CBD had been hired in 1996 in production control, and had an estimated average exposure of 0.08 μg/m[3].  He was diagnosed with CBD in 1997.  Based on samples from the 1998 to 1999 period and one sample from the 1980 to 1995 period (0.04 μg/m[3]), this job appeared to have very low exposures (1998 to 1999 mean = 0.07 μg/m[3], 95[th] percentile = 0.15 μg/m[3], max = 0.16 μg/m[3]).
      The second quartile of LTW average exposure (0.081 - 0.18 μg/m[3]) shows a marked rise in overall prevalence of beryllium-related health effects, with six workers sensitized (8.2%), of whom four were diagnosed with CBD (5.5%).  Three of the workers with CBD and one worker who was sensitized only had been hired before the mid-1990s, in periods with sparse exposure sampling.  The remaining two workers were hired in the 1998 to 1999 period and the 2000 to 2003 period, respectively, and had well-characterized LTW average exposures of 0.12 μg/m[3] and 0.18 μg/m[3], respectively.  Among six sensitized workers in the third quartile (0.19 - 0.51 μg/m[3]), all were diagnosed with CBD (7.8%).  Another increase in prevalence is seen from the third to the fourth quartile, with 12 cases of sensitization (15.4%), including 8 diagnosed with CBD (10.3%).
	When workers' HEJ exposures are considered, the exposure-response pattern is similar to that for LTW average exposure in the lower quartiles.  The lowest prevalence is observed in the first quartile (0.0 - 0.086 μg/m[3]), with increasing prevalence from first to second and second to third exposure quartiles.  The prevalence of sensitization and CBD in the top quartile (0.954 - 2.213 μg/m[3]) decreases relative to the third, with levels similar to the overall prevalence in the data set.
	The quartile analysis of cumulative exposure also shows generally, but not uniformly, increasing prevalence of sensitization and CBD with increasing exposure.  As shown in Table 8, the lowest prevalences of CBD and sensitization are in the first two quartiles of cumulative exposure (0.0 - 0.147 μg/m[3]-years, 0.148 - 1.467 μg/m[3]-years).  However, the prevalence of sensitization and CBD did not increase from the first to the second quartile.  The upper bound of the first quartile, 0.147 μg/m[3]-yrs, is approximately the cumulative exposure that a worker would have if exposed to beryllium at a level of 0.03 μg/m[3] for a working lifetime of 45 years; 0.15 μg/m[3] for 10 years; or 0.3 μg/m[3] for five years.
	A sharp increase in prevalence of CBD and total sensitization occurs between the second and third quartile (1.468 - 7.008 μg/m[3]-years) of cumulative beryllium exposure.  Cumulative exposures in the third quartile would be experienced by a worker exposed to levels between 0.03 and 0.16 μg/m3 for 45 years; 0.15 and 0.7 μg/m3 for 10 years; or 0.3 and 1.4 μg/m3 for five years.  Roughly similar levels of both sensitization and CBD occur in the highest quartile (7.009 - 61.86 μg/m[3]-years).

4. Preliminary Statistical Analysis
	A statistical modeling analysis of the NJH data set was conducted under contract with Dr. Roslyn Stone of the University of Pittsburgh Graduate School of Public Heath, Department of Biostatistics.  Dr. Stone used statistical modeling approaches to characterize risk of sensitization and CBD among workers exposed to the preceding TWA PEL, the final TWA PEL, and each of the alternate TWA PELs that were considered for the revised beryllium rule.  Asymptotic logistic regression models provided an initial review of the data set.  This was followed up with a more rigorous statistical analysis using a proportional hazards model to develop quantitative risk estimates for sensitization and CBD at the preceding TWA PEL, the final TWA PEL, and the alternate TWA PELs considered by OSHA.

Logistic Regression Models

	As a preliminary look at exposure-response patterns within the data set, logistic regression models were fit to two health endpoints: (1) CBD and (2) sensitization (including sensitized individuals with and without CBD).  Since only seven workers were reported as sensitized without CBD, this endpoint was not included in the statistical modeling.  Predictors tested in the models included cumulative and time-weighted average exposure measures, as well as total duration of exposure.  For average and HEJ exposure measures, models were also fit with exposure categories: 0.00 - < 0.05, 0.05 - < 0.1, 0.1 - < 0.2, 0.2 - < 0.5, 0.5 - < 1.0, 1.0 - < 2.0, and > 2.0.  A categorical analysis was also used for years of exposure: 0 - <1, 1 - < 10, 10 - < 20, and > 20 years.  The results of the categorical analyses were similar to those using continuous exposure values, and are not reported.
	The results of the logistic regression showed a significant (p < 0.05) positive association between sensitization and cumulative exposure to beryllium, total years of exposure, and the average exposure weighted by years spent at each job, as shown in Tables 10 to 13 below.  HEJ exposure was not as strongly related to sensitization in this model.
      Table 10. Logistic Regression: Cumulative Exposure, Sensitization Endpoint

                                  Coefficient
                                  Std. Error
                                       z
                                   P>|z|
                            95% confidence interval
                                                      Exposure (μg/m[3]-years)
                                     0.03
                                     0.015
                                     2.15
                                     0.03
                                 0.003 - 0.63
                                                                       constant
                                     -2.69
                                     0.247
                                    -10.86
                                   <0.001
                                 -3.17 - -2.20
                                                                 Log-likelihood
                                    -88.72

  Table 11. Logistic Regression: LTW Average Exposure, Sensitization Endpoint

                                  Coefficient
                                  Std. Error
                                       Z
                                   P>|z|
                            95% confidence interval
                                                            Exposure (μg/m[3])
                                     0.92
                                     0.372
                                     2.46
                                     0.01
                                  0.19 - 1.65
                                                                       constant
                                     -2.85
                                     0.284
                                    -10.03
                                   <0.001
                                 -3.40 - -2.29
                                                                 Log-likelihood
                                    -88.06

      Table 12. Logistic Regression: HEJ Exposure, Sensitization Endpoint

                                  Coefficient
                                  Std. Error
                                       Z
                                   P>|z|
                            95% confidence interval
                                                            Exposure (μg/m[3])
                                     0.48
                                     0.279
                                     1.72
                                     0.09
                                 -0.07 - 1.03
                                                                       constant
                                     -2.78
                                     0.283
                                     -9.83
                                   <0.001
                                 -3.34 - -2.23
                                                                 Log-likelihood
                                    -90.48

   Table 13. Logistic Regression: Exposure Duration, Sensitization Endpoint

                                  Coefficient
                                  Std. Error
                                       Z
                                   P>|z|
                            95% confidence interval
                                                               Exposure (years)
                                     0.04
                                     0.019
                                     2.12
                                     0.03
                                 0.003 - 0.08
                                                                       constant
                                     -3.03
                                     0.357
                                     -8.49
                                   <0.001
                                 -3.73 - -2.33
                                                                 Log-likelihood
                                    -89.59

	As shown in Tables 14 to 17 below, risk of CBD also increased with exposure duration (total years of exposure, p = 0.02), and with cumulative beryllium exposure (p = 0.04).  Unlike beryllium sensitization, CBD was only weakly associated with average exposure and HEJ exposure in the logistic model (p = 0.12 and p = 0.39, respectively).

       Table 14. Logistic Regression: Cumulative Exposure, CBD Endpoint

                                  Coefficient
                                  Std. Error
                                       Z
                                   P>|z|
                            95% confidence interval
                                                      Exposure (μg/m[3]-years)
                                     0.03
                                     0.02
                                     2.03
                                     0.04
                                 0.001 - 0.07
                                                                       Constant
                                     -3.04
                                     0.29
                                    -10.59
                                   <0.001
                                 -3.60 - -2.48
                                                                 Log-likelihood
                                    -70.76

       Table 15. Logistic Regression: LTW Average Exposure, CBD Endpoint

                                  Coefficient
                                  Std. Error
                                       Z
                                   P>|z|
                            95% confidence interval
                                                            Exposure (μg/m[3])
                                     0.69
                                     0.44
                                     1.57
                                     0.12
                                 -0.17 - 1.56
                                                                       constant
                                     -3.08
                                     0.32
                                     -9.55
                                   <0.001
                                 -3.71 - -2.44
                                                                 Log-likelihood
                                    -71.38

           Table 16. Logistic Regression: HEJ Exposure, CBD Endpoint

                                  Coefficient
                                  Std. Error
                                       Z
                                   P>|z|
                            95% confidence interval
                                                            Exposure (μg/m[3])
                                     0.29
                                     0.34
                                     0.86
                                     0.39
                                 -0.37 - 0.96
                                                                       constant
                                     -3.00
                                     0.32
                                     -9.37
                                   <0.001
                                 -3.62 - -2.37
                                                                 Log-likelihood
                                    -72.92

        Table 17. Logistic Regression: Exposure Duration, CBD Endpoint

                                  Coefficient
                                  Std. Error
                                       Z
                                   P>|z|
                            95% confidence interval
                                                               Exposure (years)
                                     0.05
                                     0.02
                                     2.33
                                     0.020
                                  0.01 - 0.10
                                                                       constant
                                     -3.56
                                     0.44
                                     -8.08
                                   <0.001
                                 -4.42 - -2.69
                                                                 Log-likelihood
                                    -70.52

	Dr. Stone performed the logistic regressions as a simple first analysis of the data.  Although relatively simple to interpret, standard logistic regression has substantial limitations in the present setting and is not a fully appropriate approach for analysis of this data set.  Logistic regression models the probability of an event in a fixed period of time.  As such, logistic regression cannot account for essential features of these data, specifically, differential time at risk and changing exposures over time. OSHA therefore did not use the results of the logistic regression to create quantitative risk estimates for beryllium sensitization and CBD.  Dr. Stone developed a proportional hazards model, a more appropriate model form for this data set, as a basis for the Agency's preliminary quantitative risk estimates.

Discrete Time Proportional Hazards Analysis
	Dr. Stone performed an exposure-response analysis of the NJH data set using a discrete time proportional hazards analysis (DTPHA), which was presented in section VI of the proposed rule and in a technical document (OSHA, 2014, Document ID 1589).  The DTPHA is an extension of logistic regression that allows for time-dependent exposures and differential time at risk.  It accounts for the fact that individuals in the data set are followed for different amounts of time, and that their exposures change over time.  The DTPHA is a discrete-time analog to the Cox proportional hazards model for continuous time, and was considered to be appropriate by Dr. Stone because diagnosis dates are known only to the nearest year.  In addition, where logistic regression yields odds ratios, the proportional hazards model provides hazard ratios (HRs).
	To perform this analysis, ERG constructed exposure files in Excel with cumulative and average exposures for each worker in the data set in each year that a case of sensitization or CBD was identified.  Separate files were constructed for two outcomes, sensitization (26 cases, including all cases of CBD) and diagnosed CBD (19 cases).  This analysis focuses on cumulative and long-term (eight-hour) time-weighted average (LTWA) exposure measures, as well as duration of exposure (in years).  All exposures were treated as continuous variables. A negative value for cumulative exposure for one worker, the result of an error in the data set, was set to 0.

      The time-specific risk sets were defined as follows.  Time-dependent exposures were estimated for each worker "at risk."  In the file constructed for the sensitization exposure-response analysis, workers were considered to be at risk from the time of hire at the plant until the end of their employment or their identification as a sensitized worker, whichever came earlier.  Thus, workers found to have sensitization or CBD were considered to be at risk until the reported time of sensitization, or the time of diagnosed CBD for those CBD cases who were identified as sensitized in the same round of testing that they were diagnosed with CBD.  Those three workers who were first identified as sensitized only and later diagnosed with CBD were considered to be at risk until the reported time of sensitization.  The "sensitization" outcome was coded as missing in years following sensitization, so such observations would be dropped from the analysis.
	Similarly, in the file constructed for the CBD exposure-response analysis, workers were considered to be at risk from the time of hire at the plant until the end of their employment or their CBD diagnosis.  Workers diagnosed with CBD were considered to be at risk until the reported time of diagnosis. Those who were first identified as sensitized only and later diagnosed with CBD were considered to be at risk until the diagnosis of CBD.  Workers who were not diagnosed with CBD were considered at risk until their last date of observation (the last year of employment from their work history).  The "CBD" outcome was coded as missing in years following diagnosis, so such observations would be dropped from the analysis.
	For each year that a given worker is at risk for an outcome, ERG created a vector of variables denoting the case status and the values of the exposure variables for the worker at that time.  Data were converted from Excel to Stata for statistical analysis using Stat Transfer, version 8, and read into Stata SE version 10.
	The DTPHA is the discrete time counterpart of the Cox model (Document ID 1660, p. 9).    Instead of the continuous baseline hazard that is estimated indirectly in the Cox model, the DTPHA explicitly estimates the baseline hazard using dummy variables for time.  For sensitization models, dummy variables were generated for each of the years in which a sensitized worker was identified.  For CBD models, there were dummy variables for each of the years in which a worker was diagnosed with CBD.
The DTPHA model is:
                      log(-log (1-pit))) = β0t + β1Xit
where pit is the probability of sensitization or CBD at time t, β0t is the time-specific intercept, β1 is the exposure coefficient, and Xit is the exposure for worker i at time t.  The time-specific intercept β0t was modeled as a constant plus dummy variables for the non-reference diagnosis year.  The exponentiated β1 coefficient in the proportional hazards model is interpreted as the HR per unit change in X (for continuous exposures) or the HR comparing level X to the reference level (for categorical exposures).  Exposures were treated as continuous variables for this analysis.  These models were fit using maximum likelihood estimation implemented in standard generalized linear model software.  The assumed linearity was checked using fractional polynomials.
	In the course of preparing the data set for preliminary statistical analysis, ERG discovered that regular upkeep of the work-history records was maintained only through 2003.  Beginning in 2004, maintenance of the work-history records became uneven, and ERG found several errors in the post-2003 portion of work-history records (see OSHA, 2014, Document ID 1589).  Dr. Stone therefore performed analyses truncating exposure, work history, and screening history at 2002 (the last year before 2004 that any cases were identified).  As five workers with sensitization and CBD were identified in 2004 and 2005, the truncated analysis included fewer cases of sensitization and CBD than the analysis using post-2003 data.

Preliminary Models
	The exposure-response models resulting from the discrete proportional hazards analyses, based on the data set including cases diagnosed in 2004 and 2005, are presented in Tables 18 to 25 below.  All coefficients used in the models are displayed, including the exposure coefficient, the model constant, and additional coefficients for year of diagnosis fit in the proportional hazards modeling procedure.
                Table 18. Cumulative Exposure and Sensitization

                                   Variable
                                  Coefficient
                            95% confidence interval
                                    P-value
                                              Cumulative Exposure (μg/m3 -yrs)
                                                                           0.03
                                -0.003 to 0.06
                                                                           0.08
                                                                       Constant
                                                                          -3.43
                                -4.20 to -2.66
                                                                      <0.001
                                                                           1996
                                                                          -1.49
                                 -3.04 to 0.06
                                                                           0.06
                                                                           1997
                                                                          -0.30
                                 -1.31 to 0.72
                                                                           0.57
                                                                           1998
                                                                          -1.57
                                -3.12 to -0.02
                                                                           0.05
                                                                           1999
                                                                          -1.58
                                -3.13 to -0.03
                                                                           0.05
                                                                           2004
                                                                          -1.77
                                -3.33 to -0.22
                                                                           0.03
                                                                           2005
                                                                          -1.37
                                -2.70 to -0.03
                                                                           0.04

               Table 19. LTW Average Exposure and Sensitization
                                   Variable
                                  Coefficient
                            95% confidence interval
                                    P-value
                                                    Average Exposure (μg/m[3])
                                                                           0.44
                                 -0.18 to 1.05
                                                                           0.16
                                                                       Constant
                                                                          -3.47
                                -4.31 to -2.63
                                                                      <0.001
                                                                           1996
                                                                          -1.49
                                 -3.04 to 0.06
                                                                           0.06
                                                                           1997
                                                                          -0.30
                                 -1.32 to 0.72
                                                                           0.56
                                                                           1998
                                                                          -1.56
                                -3.11 to -0.004
                                                                           0.05
                                                                           1999
                                                                          -1.55
                                -3.11 to 0.002
                                                                           0.05
                                                                           2004
                                                                          -1.73
                                -3.30 to -0.16
                                                                           0.03
                                                                           2005
                                                                          -1.32
                                 -2.66 to 0.03
                                                                           0.06

                   Table 20. HEJ Exposure and Sensitization

                                   Variable
                                  Coefficient
                            95% confidence interval
                                    P-value
                                                        HEJ Exposure (μg/m[3])
                                                                           0.20
                                 -0.34 to 0.75
                                                                           0.47
                                                                       Constant
                                                                          -3.33
                                -4.15 to -2.51
                                                                      <0.001
                                                                           1996
                                                                          -1.50
                                 -3.05 to 0.05
                                                                           0.06
                                                                           1997
                                                                          -0.32
                                 -1.33 to 0.70
                                                                           0.54
                                                                           1998
                                                                          -1.60
                                -3.15 to -0.05
                                                                           0.04
                                                                           1999
                                                                          -1.62
                                -3.17 to -0.06
                                                                           0.04
                                                                           2004
                                                                          -1.82
                                -3.38 to -0.27
                                                                           0.02
                                                                           2005
                                                                          -1.41
                                -2.74 to -0.08
                                                                           0.04

                 Table 21. Exposure Duration and Sensitization

                                   Variable
                                  Coefficient
                            95% confidence interval
                                    P-value
                                                      Exposure Duration (years)
                                                                           0.04
                                -0.009 to 0.08
                                                                           0.11
                                                                       Constant
                                                                          -3.68
                                -4.63 to -2.72
                                                                      <0.001
                                                                           1996
                                                                          -1.47
                                 -3.02 to 0.08
                                                                           0.06
                                                                           1997
                                                                          -0.29
                                 -1.30 to 0.73
                                                                           0.58
                                                                           1998
                                                                          -1.58
                                -3.13 to -0.03
                                                                           0.05
                                                                           1999
                                                                          -1.62
                                -3.17 to -0.07
                                                                           0.04
                                                                           2004
                                                                          -1.84
                                -3.39 to -0.29
                                                                           0.02
                                                                           2005
                                                                          -1.42
                                -2.75 to -0.10
                                                                           0.04

	As shown in Tables 18 to 21 above, relative risk of beryllium sensitization increased with cumulative exposure, LTW average exposure, HEJ exposure, and exposure duration, but the relationships were not statistically significant.
	The models for the CBD endpoint (Tables 22 to 25 below) using data through 2005 also showed positive, but not statistically significant relationships between the relative risk of CBD and cumulative exposure, LTW average exposure, and HEJ exposure.  A significant positive association was observed between duration of exposure and CBD (p = 0.04).

                    Table 22.  Cumulative Exposure and CBD

Variable
                                  Coefficient
                            95% confidence interval
                                    P-value
                                              Cumulative Exposure (μg/m3 -yrs)
                                                                           0.03
                                 -0.01 to 0.06
                                                                           0.09
                                                                       Constant
                                                                          -3.75
                                -4.64 to -2.86
                                                                      <0.001
                                                                           1997
                                                                          -0.59
                                 -1.86 to 0.67
                                                                           0.36
                                                                           1998
                                                                          -2.01
                                 -4.13 to 0.10
                                                                           0.06
                                                                           1999
                                                                          -0.63
                                 -1.90 to 0.63
                                                                           0.33
                                                                           2002
                                                                          -2.13
                                -4.25 to -0.01
                                                                           0.05
                                                                           2004
                                                                          -2.19
                                -4.31 to -0.07
                                                                           0.04
                                                                           2005
                                                                          -1.49
                                 -3.10 to 0.11
                                                                           0.07

                    Table 23. LTW Average Exposure and CBD

                                   Variable
                                  Coefficient
                            95% confidence interval
                                    P-value
                                               Average Exposure (μg/m[3] -yrs)
                                                                           0.19
                                 -0.61 to 0.99
                                                                           0.58
                                                                       Constant
                                                                          -3.59
                                -4.54 to -2.63
                                                                      <0.001
                                                                           1997
                                                                          -0.61
                                 -1.88 to 0.66
                                                                           0.34
                                                                           1998
                                                                          -2.03
                                 -4.15 to 0.11
                                                                           0.09
                                                                           1999
                                                                          -0.65
                                 -1.92 to 0.62
                                                                           0.32
                                                                           2002
                                                                          -2.17
                                -4.30 to -0.04
                                                                           0.05
                                                                           2004
                                                                          -2.23
                                -4.37 to -0.10
                                                                           0.04
                                                                           2005
                                                                          -1.54
                                 -3.15 to 0.03
                                                                           0.08

                        Table 24. HEJ Exposure and CBD
                                   Variable
                                  Coefficient
                            95% confidence interval
                                    P-value
                                                   HEJ Exposure (μg/m[3] -yrs)
                                                                           0.02
                                 -0.67 to 0.71
                                                                           0.96
                                                                       Constant
                                                                          -3.48
                                 -4.42 to 2.55
                                                                      <0.001
                                                                           1997
                                                                          -0.62
                                 -1.88 to 0.65
                                                                           0.34
                                                                           1998
                                                                          -2.05
                                 -4.16 to 0.07
                                                                           0.06
                                                                           1999
                                                                          -0.68
                                 -1.95 to 0.59
                                                                           0.29
                                                                           2002
                                                                          -2.21
                                -4.33 to -0.09
                                                                           0.04
                                                                           2004
                                                                          -2.28
                                -4.40 to -0.16
                                                                           0.04
                                                                           2005
                                                                          -1.58
                                 -3.19 to 0.02
                                                                           0.05

                     Table 25.   Exposure Duration and CBD
                                   Variable
                                  Coefficient
                            95% confidence interval
                                    P-value
                                                      Exposure Duration (years)
                                                                           0.06
                                -0.001 to -0.11
                                                                           0.04
                                                                       Constant
                                                                          -4.24
                                -5.39 to -3.10
                                                                      <0.001
                                                                           1997
                                                                          -0.57
                                 -1.84 to 0.69
                                                                           0.38
                                                                           1998
                                                                          -2.01
                                 -4.13 to 0.11
                                                                           0.06
                                                                           1999
                                                                          -0.67
                                 -1.94 to 0.59
                                                                           0.30
                                                                           2002
                                                                          -2.23
                                -4.34 to -0.11
                                                                           0.04
                                                                           2004
                                                                          -2.27
                                -4.38 to -0.15
                                                                           0.04
                                                                           2005
                                                                          -1.57
                                 -3.17 to 0.03
                                                                           0.06

	As discussed previously, ERG discovered several errors in the last years of work history (2004-2005) in the NJH data set.  To test whether excluding these years would affect the model results, Dr. Stone conducted an analysis on a subcohort of workers hired prior to 2003, truncating work histories and screening histories at the end of 2002.  This analysis showed that truncating the analysis at 2002 appeared to affect models that use beryllium sensitization as the endpoint, as shown in Tables 26 to 29 below.  The truncated data set was smaller than the full data set and included fewer cases of sensitization.  It might therefore be expected to yield a less statistically significant exposure coefficient than the full data set.  However, the p-values associated with the exposure coefficients were lower in the truncated data set than in the full data set for the cumulative, LTW average, and HEJ exposure measures.  Thus, truncating the data set at 2002, before the point when work histories were no longer reliably updated, may have reduced the amount of error in the Cullman workers' exposure estimates.
	Similar to the full cohort analysis, relative risk of sensitization increased with cumulative exposure, LTW average exposure, HEJ exposure, and exposure duration in the analysis of the subcohort.  The relationship was borderline statistically significant (p = 0.05) in the cumulative exposure analysis truncated in 2002.  In the other models, the relationship was not statistically significant.  However, the model using average exposure and truncated at 2002 was suggestive of a relationship between average exposure and relative risk of sensitization (p = 0.09).  The association was much weaker for exposure duration (p = 0.31), consistent with the expected biological action of an immune hypersensitivity response where onset is believed to be more dependent on the concentration of the sensitizing agent at the target site rather than the number of years of occupational exposure.  The association was also much weaker for HEJ exposure (p = 0.3).
               Table 26.  Cumulative Exposure and Sensitization
                                   Variable
                                  Coefficient
                            95% confidence interval
                                    P-value
                                              Cumulative Exposure (μg/m3 -yrs)
                                                                          0.031
                                -0.001 to 0.063
                                                                           0.05
                                                                       Constant
                                                                          -3.48
                                -4.27 to -2.69
                                                                      <0.001
                                                                           1996
                                                                          -1.49
                                 -3.04 to 0.06
                                                                           0.06
                                                                           1997
                                                                          -0.29
                                 -1.31 to 0.72
                                                                           0.57
                                                                           1998
                                                                          -1.56
                                -3.11 to -0.01
                                                                           0.05
                                                                           1999
                                                                          -1.57
                                -3.12 to -0.02
                                                                           0.05

                 Table 27.  Average Exposure and Sensitization

                                   Variable
                                  Coefficient
                            95% confidence interval
                                    P-value
                                                    Average Exposure (μg/m[3])
                                                                           0.54
                                 -0.09 to 1.17
                                                                           0.09
                                                                       constant
                                                                          -3.55
                                -4.42 to -2.69
                                                                      <0.001
                                                                           1996
                                                                          -1.48
                                 -3.03 to 0.07
                                                                           0.06
                                                                           1997
                                                                          -0.29
                                 -1.31 to 0.72
                                                                           0.57
                                                                           1998
                                                                          -1.54
                                 -3.09 to 0.01
                                                                           0.05
                                                                           1999
                                                                          -1.53
                                 -3.08 to 0.03
                                                                           0.05

                   Table 28.  HEJ Exposure and Sensitization
                                   Variable
                                  Coefficient
                            95% confidence interval
                                    P-value
                                                        HEJ Exposure (μg/m[3])
                                                                           0.31
                                 -0.27 to 0.88
                                                                           0.30
                                                                       constant
                                                                          -3.42
                                -4.27 to -2.56
                                                                      <0.001
                                                                           1996
                                                                          -1.49
                                 -3.04 to 0.06
                                                                           0.06
                                                                           1997
                                                                          -0.31
                                 -1.33 to 0.70
                                                                           0.55
                                                                           1998
                                                                          -1.59
                                -3.14 to -0.04
                                                                           0.05
                                                                           1999
                                                                          -1.60
                                -3.15 to -0.05
                                                                           0.04

                Table 29.  Exposure Duration and Sensitization
                                   Variable
                                  Coefficient
                            95% confidence interval
                                    P-value
                                                      Exposure Duration (years)
                                                                           0.03
                                 -0.03 to 0.08
                                                                           0.31
                                                                       Constant
                                                                          -3.55
                                -4.57 to -2.53
                                                                      <0.001
                                                                           1996
                                                                          -1.48
                                 -3.03 to 0.70
                                                                           0.06
                                                                           1997
                                                                          -0.30
                                 -1.31 to 0.72
                                                                           0.57
                                                                           1998
                                                                          -1.59
                                -3.14 to -0.04
                                                                           0.05
                                                                           1999
                                                                          -1.62
                                -3.17 to -0.72
                                                                           0.04

	Truncating the analysis at 2002 had less of an impact on models for the CBD endpoint, as shown in Tables 30 to 33 below.  This analysis showed positive, but not statistically significant, relationships between relative risk of CBD and cumulative exposure, average exposure, HEJ exposure, and exposure duration. Similar to the initial analysis, the model using cumulative exposure was suggestive of a relationship in the analysis truncated at 2002 (p = 0.09), whereas average and HEJ exposures were not significantly related to CBD risk (p > 0.5 for all models).

                    Table 30.   Cumulative Exposure and CBD
                                                                       Variable
                                                                    Coefficient
                                                        95% confidence interval
                                                                        P-value
                                              Cumulative Exposure (μg/m3 -yrs)
                                                                           0.03
                                                                   0.00 to 0.07
                                                                           0.09
                                                                       Constant
                                                                          -3.77
                                                                 -4.67 to -2.86
                                                                      <0.001
                                                                           1997
                                                                          -0.59
                                                                  -1.86 to 0.68
                                                                           0.36
                                                                           1998
                                                                          -2.01
                                                                  -4.13 to 0.11
                                                                           0.06
                                                                           1999
                                                                          -0.63
                                                                  -1.90 to 0.64
                                                                           0.33
                                                                           2002
                                                                          -2.13
                                                                 -4.25 to -0.01
                                                                           0.05

                   Table 31.   LTW Average Exposure and CBD
                                                                       Variable
                                                                    Coefficient
                                                        95% confidence interval
                                                                        P-value
                                                LTW Average Exposure (μg/m[3])
                                                                           0.24
                                 -0.59 to 1.06