Occupational Exposures to Diacetyl and 2, 3-pentanedione

Final Document: Publication No. 2016-111: NIOSH Criteria for a Recommended Standard: Occupational Exposure to Diacetyl and 2,3-Pentanedione

Related Materials

• NIOSH Response to Peer Review Comments
• NIOSH Response to Public and Stakeholder Comments
• NIOSH Docket 245
• NIOSH Docket 245-A

Review #2, Follow-up review of new content, December 2013

Chapter 6: Quantitative Risk Assessment Based on Animal Data

Chapter 8: Hazard Prevention and Control of Exposure to Diacetyl and 2,3-Pentanedione

Cross-Clearance Agencies: None

Date of Dissemination: December 26, 2013

Subject of planned Report: Diacetyl and 2,3-pentanedione

Purpose of Planned Report: The Criteria document provides a forum to review new scientific information in regards to diacetyl and 2,3-pentanedione, and provide guidance to stakeholders, public health agencies and regulatory agencies. The entire criteria document has previously undergone external peer review and public comment from August 2011– May 2012. Peer and public review is now being completed on a revised Chapter 6 and a new section of Chapter 8 only. This new content supports the conclusions in the draft criteria document so can be reviewed independently of the entire document.

Type of Dissemination: Highly Influential

Timing of Review: Federal Register Notice posted on December 26, 2013 through February 10, 2014.

Primary Disciplines or Expertise: 1) Toxicology, 2) Risk assessment, 3) Hazard Communication

Type of Review: Third Party Review

Number of Reviewers: 4

Reviewers Selected by: Oak Ridge Institute for Science and Education (ORISE) will coordinate peer review.

Peer Reviewers

1. Dale Hattis, Ph.D.
   Academic and Professional Credentials: Research Professor, George Perkins Marsh Institute, Clark University
   Organization Affiliation: Clark University
   Area of Expertise, Discipline, or Relevant Experience: Methodology for quantitative health risk assessment for cancer and non-cancer health effects; Human inter-individual variability in susceptibility to toxic effects; Pharmacokinetic and Monte Carlo simulation modeling; Implications of inter-individual variability for population risk for both carcinogens and other toxic substances
2. Sam Kacew, Ph.D., ATS
   Academic and Professional Credentials: Associate Director of Toxicology, McLaughlin Centre for Population Health Risk Assessment; Professor, Department of Cellular & Molecular Medicine, University of Ottawa
   Organization Affiliation: University of Ottawa
   Area of Expertise, Discipline, or Relevant Experience: General toxicology and human health risk assessment, particularly renal, hepatic, and pulmonary toxicology
3. David Halton, Ph.D., CIH; CRSP
   Academic and Professional Credentials: Ph.D. in Toxicology, University of Windsor (1978); Certified Industrial Hygienist (1988); Canadian Registered Safety Professional (1991)
   Organization Affiliation: Private Consultant
   Area of Expertise, Discipline, or Relevant Experience: Toxicology and chemical hazard communication, including Globally Harmonized System (GHS); hazardous material reviews, toxicological risk assessments, industrial hygiene surveys, and safety audits
4. John Howell, Ph.D.
   Academic and Professional Credentials: Ph.D. in Inorganic Chemistry, Drexel University
   Organization Affiliation: Private Consultant
   Area of Expertise, Discipline, or Relevant Experience: Chemical hazard communication; GHS-compliant safety data sheet authoring

Peer Review Questions For Chapter 6 and Subsection of Chapter 8 of Diacetyl/ 2,3-Pentanedione criteria document

The National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention (NIOSH, CDC) is continuing the peer review process of the draft document entitled, Criteria for a Recommended Standard: Occupational Exposure to Diacetyl and 2,3-pentanedione. The entire criteria document has previously undergone external peer review and public comment from August 2011– May 2012. We are seeking external review of two revised portions of this document, including a revised Chapter 6 and a new section of Chapter 8. Descriptions of the new content for these chapters are provided with the peer review questions below for each of these chapters. This new content supports the conclusions in the draft criteria document so can be reviewed independently of the entire document.

NIOSH considers the draft Criteria Document to be a highly influential scientific assessment (HISA) containing significant guidance as defined by the OMB Peer Review Bulletin and Good Guidance Practices Bulletin. The overall goal of the peer and public reviews is to enhance the quality and credibility of NIOSH recommendations by ensuring that the scientific and technical work underlying these recommendations receives appropriate review by independent scientific and technical experts as well as public review. This charge was developed in accordance with OMB guidelines, and is consistent with NIOSH peer review practice.

Technical peer reviews are requested from persons known to be competent to appraise the scientific and technical quality of a document. The purpose of the peer review is to assess the technical validity of the information, and not matters of style or usage. If there are errors of fact, unsubstantiated claims, evidence of careless experimental work, inclusion of too much information already in the literature, or statements that are inaccurate, please note such in your review comments. We ask that special emphasis be placed on technical review of the following issues:

For Chapter 6 – Quantitative Risk Assessment Based on Animal Data:

Overview of changes: After the previous peer review and public comment process was initiated, the National Toxicology Program released a new dataset on diacetyl and 2,3-pentanedione. Chapter 6, titled Quantitative Risk Assessment Based on Animal Data, has been updated to accommodate this new dataset. The new dataset and associated quantitative risk assessment of these animal data support the previous conclusions of the human risk assessment in the original draft document.

Peer review questions:

1. Is the risk estimation for diacetyl and 2,3-pentanedione presented in Chapter 6 a reasonable reflection of the current understanding of the scientific literature?
2. The new NIOSH risk assessment estimates BMC(L)10 for more than 20 respiratory tract response endpoints in rats and mice. Which of these should be regarded as most relevant for estimating worker risk to diacetyl/2,3- pentanedione and for deriving a REL? Should the most sensitive endpoint (i.e., lowest BMC(L)10) in the most sensitive sex/species be given greatest preference? Are there other features to consider such as site of injury (e.g., bronchus vs. nose) or type of lesion? Please explain the rationale for your response.
3. The new NIOSH risk assessment relies on a computational fluid dynamics/physiologically-based pharmacokinetic (CFD/PBPK) model to determine the human equivalent concentrations (HEC) that correspond to equivalent diacetyl concentrations in the nose and tracheobronchial regions of rodent and lightly exercising workers (see tables 6-4 through 6-9). Please describe the advantages and disadvantages of using these regional rodent-to-human respiratory tissue concentration ratios as dose metrics and describe any viable alternatives.
4. The CFD/PBPK model is also able to predict exposure levels corresponding to diacetyl concentrations in human bronchiolar tissue. How much value would be realized by adding HECs that correspond to the human bronchiolar region to the analysis (based on the assumption that bronchiolar tissue is a target for flavoring-related constrictive bronchiolitis reported in workers)?
5. The animal-to-human dose adjustment factors used in the assessment are based on modeling at a single diacetyl exposure level (1 ppm) under one condition of nasal/mouth breathing. Are there other dose adjustment factors that would provide useful information on human risks based on modeling different diacetyl exposures or greater rates of mouth breathing? What value would those analyses add to the current risk assessment?
6. The new NIOSH risk assessment uses a mouse-to-human dose adjustment factor that assumes a mouse minute volume (VE) based on allometric scaling instead of the 2- to 4-fold higher VE values previously measured in diacetyl-exposed male mice (see 8/2011 external review draft, Appendix 6-A Table 8). Would an extension of the analysis to include basing the dose adjustment factors on the measured mouse minute volume estimates contribute significant value to the present risk assessment? Please explain any additional insight these analyses might offer?
7. The new NIOSH risk assessment applies a series of UFs to the calculated HEC that account for rodent-to-human differences in target tissue sensitivity (UF = 2.5), variability in diacetyl-induced respiratory toxicity in the worker population (UF = 3.2), and extrapolation from a 13-week subchronic exposure study to chronic 45-year working lifetime (UF = 3). The resulting aggregate UF of 24 was used to estimate animal-based candidate RELs. Have the selection and magnitude of the various UFs been adequately described based on best available scientific evidence and/or accepted scientific practice? What other factors for intraspecies variability could be considered to account for the variable susceptibility in impaired pulmonary function among exposed microwave popcorn workers discussed in Chapter 5 (Quantitative Risk Assessment Based on Worker Data)?
8. While the new NIOSH risk assessment uses the deterministic UF approach to derive candidate RELs, the previous risk assessment presented in the 2011 NIOSH external review draft (/niosh/docket/archive/pdfs/NIOSH-245/DraftDiacetylCriteriaDocument081211.pdf) used best-fitting probabilistic models to derive risk–specific exposure levels, such as the projected REL corresponding to a 1 in 1000 risk. Is there significant value to adding a quantitative model-derived risk assessment of rodent respiratory tract toxicity as a complement to the primary exposure –response assessment derived from occupational epidemiology investigations?
9. The relative potency of 2,3- pentanedione from a two week inhalation study in mice and diacetyl from the 13-week inhalation study in mice were jointly analyzed across multiple common respiratory tract endpoints using cumulative logistic models. NIOSH concludes that the modeling results suggest that "it would be prudent to treat 2,3- pentanedione as at least as toxic as diacetyl." Please comment on the validity and utility of the methods used to support this interpretation.

For Chapter 8 – GHS section

Overview of changes:

After the previous peer review and public comment process was initiated, the Occupational Safety and Health Administration (OSHA) promulgated a revised Hazard Communication Standard aligned with the Globally Harmonized System of Classification and Labeling of Chemicals (GHS). The new section of Chapter 8 includes classifications of these chemicals based on the OSHA GHS criteria. These classifications were added in response to some of the comments received during the public and peer review comment period for the draft criteria document. It is of note that this is the first time that a NIOSH document has provided GHS classifications that were derived by NIOSH. Though other NIOSH documents have previously published GHS classifications (e.g. NIOSH Skin Notations), those GHS classifications were derived by and cited from another authoritative body. Peer review questions:

1. In the updated hazard communication chapter of the diacetyl/2,3- pentanedione Criteria Document, NIOSH has provided Globally Harmonized System of Classification and Labeling (GHS) classifications based on the revised Occupational Safety and Health Administration (OSHA) Hazard Communication (HazCom) Standard (29 CFR 1910.1200). Do these classifications reflect a reasonable interpretation of the peer-reviewed data that are presented? Is this section a reasonable reflection of the current understanding of the scientific literature?
2. As part of the OSHA HazCom Standard, labeling of chemicals that are part of mixtures is only required if the hazardous chemicals in the mixture are present in bulk concentrations above specific "cut-off" values outlined in Appendix A of the OSHA HazCom Standard. These cut-off values vary by health endpoint. In the case of diacetyl, it has been observed on several occasions (outlined in the document) that air concentrations of diacetyl exceeded the proposed NIOSH REL, when bulk concentrations of diacetyl in the source mixtures were below the cut-off values prescribed in the OSHA HazCom Standard. NIOSH has described why following these cut-off values for mixtures containing diacetyl will sometimes not alert workers to potential exposures to diacetyl above the proposed REL. Please comment on the rationale NIOSH described. Has NIOSH provided adequate information to support why these cut-off values should be lowered in the specific case of diacetyl? NIOSH has extended this approach to 2,3-pentanedione. Please comment on the rationale NIOSH used to justify this approach. What additional data are available that would inform NIOSH's reasoning on this issue?
3. Is the current level of detail and explanation for how GHS hazard classifications were derived in the HazCom section of the criteria document sufficient? If not, what additional information would be useful?

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Review #1, Initial review, Completed 2011:

Title: Criteria for a Recommended Standard: Occupational Exposures to Diacetyl and 2, 3-pentanedione

Cross-Clearance Agencies: None

Anticipated Date of Dissemination: August 12, 2011

Subject of planned Report: Diacetyl and 2,3-pentanedione

Purpose of Planned Report: The Criteria document provides a forum to review new scientific information, develop a recommended exposure limit for diacetyl and 2,3-pentanedione, and provide guidance to stakeholders, public health agencies and regulatory agencies.

Type of Dissemination: Highly Influential

Timing of Review: Federal Register Notice posted July 25, 2011 and October 18, 2011, Public Meeting August 26, 2011

Primary Disciplines or Expertise: 1) Medical Aspects and Toxicology, 2) Risk Assessment, 3) Exposure Assessment and Hazard Control

Type of Review: Third Party Review

Anticipated Number of Reviewers: 6

Reviewers Selected by: Oak Ridge Institute for Science and Education (ORISE) will coordinate peer review

Peer Reviewers

1. Jonathan Borak, M.D.
   Academic and Professional Credentials: Clinical Professor of Medicine, Yale University; Clinical Professor of Epidemiology & Public Health, Yale University; Adjunct Associate Professor of Medicine, Johns Hopkins University; President, Jonathan Borak & Company
   Organization Affiliation: Yale University
   Area of Expertise, Discipline, or Relevant Experience: Risk Assessment, Occupational Medicine/Toxicology
2. Mark Cullen, M.D.
   Academic and Professional Credentials: Professor of Medicine and Chief, Division of General Medicine and Associate, Center for Health Policy, Stanford School of Medicine
   Organization Affiliation: Stanford University
   Area of Expertise, Discipline, or Relevant Experience: Occupational and Environmental Medicine
3. Yiliang Zhu, Ph.D.
   Academic and Professional Credentials: Professor, College of Public Health, University of South Florida
   Organization Affiliation: University of South Florida
   Area of Expertise, Discipline, or Relevant Experience: Biostatistics/Risk Assessment
4. Arthur Frank, MD, Ph.D.
   Academic and Professional Credentials: Professor of Public Health, Department of Environmental and Occupational Health, Drexel University
   Organization Affiliation: Drexel University
   Area of Expertise, Discipline, or Relevant Experience: Occupational Medicine/Toxicology
5. Harvey Checkoway, Ph.D.
   Academic and Professional Credentials: Professor, Departments of Environmental Health and Epidemiology, University of Washington, School of Public Health & Community Medicine
   Organization Affiliation: University of Washington
   Area of Expertise, Discipline, or Relevant Experience: Epidemiology
6. Warren Myers, Ph.D.
   Academic and Professional Credentials: Professor and Associate Dean for Academic Affairs for the College of Engineering and Mineral Resources, West Virginia University
   Organization Affiliation: West Virginia University
   Area of Expertise, Discipline, or Relevant Experience: Exposure Assessment/Hazard Controls

Public Nominations Requested for Reviewers: No

Opportunities for the Public to Comment: Yes
Oral comments before peer review panel, August 26, 2011
Written comments to peer reviewers, November 30, 2011
Publication of a request for public comment, July 25, 2011

Peer Reviewers Provided with Public Comments before Their Review: Yes

Charge to Peer Reviewers

Charge for external review of draft NIOSH Criteria document Criteria for a Recommended Standard Occupational Exposure to Diacetyl and 2,3-pentanedione.

The National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention (NIOSH, CDC) is continuing the peer review process of the draft document entitled, Criteria for a Recommended Standard Occupational Exposure to Diacetyl and 2,3-pentanedione.

NIOSH considers the draft Criteria Document to be a highly influential scientific assessment (HISA) containing significant guidance as defined by the OMB Peer Review Bulletin and Good Guidance Practices Bulletins. The overall goal of the peer and public review is to enhance the quality and credibility of NIOSH recommendations by ensuring that the scientific and technical work underlying these recommendations receives appropriate review by independent scientific and technical experts as well as public review. This charge was developed in accordance with OMB guidelines, and is consistent with NIOSH peer review practice.

Technical peer reviews are requested from persons known to be competent to appraise the scientific and technical quality of a document. The purpose of the peer review is to assess the technical validity of the information, and not matters of style or usage. If there are errors of fact, unsubstantiated claims, evidence of careless experimental work, inclusion of too much information already in the literature, or statements that are inaccurate, please note such in your review comments. We ask that special emphasis be placed on technical review of the following issues:

1. Whether the health hazard identification, risk estimation, and discussion of health effects of diacetyl and 2,3-pentanedione a reasonable reflection of the current understanding of the scientific literature;
2. Are there additional critical studies relevant to occupational exposure to diacetyl and 2,3-pentanedione that should be included?
3. Whether the recommended strategies for controlling or preventing exposure to diacetyl and 2,3-pentanedione (e.g., engineering controls, work practices, medical surveillance, personal protective equipment) are reasonable;
4. Does NIOSH have a transparent and sound basis for its revised Recommended Exposure Limit for diacetyl and 2,3-pentanedione?
5. In the quantitative risk assessment, should NIOSH consider a 10-year duration of exposure instead of a 45-year duration?
6. Are there additional recommendations for worker protection that should be included?

Additional Questions for the Peer Reviewers

After consultation with the Occupational Safety and Health Administration, we ask that peer reviewers also consider the following questions:

1. NIOSH combined exposure - response data from plants K and L in order to enhance statistical power of the risk analysis, but did not include data from Plant G in the pooled analysis because: (a) the butter flavor mixing and storage tanks (primary source of airborne diacetyl) were not isolated from the other production areas; (b) the average diacetyl air levels in production and quality control were substantially higher; (c) the exposure coefficients from regression models were substantially lower, and (d) multiple exposure and medical surveys were conducted while/after controls were implemented.

   What is the utility of grouping exposure - response data for companies K and L? How else might the exposure-responses from different company data sets be combined? Would it be useful to conduct risk analysis on a grouped data set that contains exposure-response for all three plants?

2. NIOSH chose two case definitions based on spirometry measures for incidence rate modeling of discrete adverse outcomes. The more restrictive definition, FEV1<LLN and FEV1/FVC<LLN, is widely regarded as a functional measure of pulmonary obstruction. NIOSH also used a more general spirometry measure of abnormal lung function, FEV1<LN in the analysis.

   Are these outcomes informative as case definitions for modeling diacetyl-induced pulmonary impairment? FEV1/FVC<LLN is a condition widely regarded to define borderline airways obstruction. What value would be gained by using this spirometry measure as a less restrictive case definition? Are there any disadvantages of including such an analysis?

3. Many workers who met the case-qualifying spirometry failed to recall any associated symptoms (e.g., shortness of breath, chest tightness, etc.) prior to the date of first qualifying spirometry result. These asymptomatic subjects were excluded from the incidence rate modeling because of the difficulties encountered with establishing the date of onset. As a result, the number of incident cases for analysis was cut in half (e.g., N=19 instead of N=40; see section 5.2.2)

   What is the anticipated impact of this exclusion criterion on the estimates of lifetime risk? Would an alternate risk analysis that includes the asymptomatic subjects with impaired pulmonary function provide useful risk assessment information? How could the asymptomatic individuals best be included in such an analysis? What are the advantages and disadvantages to such an approach?

4. The incidence rate models that used the cumulative exposure metric also included a covariate for employment duration. One concern that has been raised about using this approach is the impact of collinearity on the final risk numbers. Please share your opinion about the advantages and disadvantages of including both cumulative exposure and a duration term in the same model. Are issues regarding collinearity adequately explained in the document, since CumExp = Dur x AvgExp? If not, what additional explanation is needed?

5. Cumulative exposure is considered the exposure metric of choice for quantitative risk assessment from diacetyl exposure. However, average exposure determined over one's employment duration since start of diacetyl use was also found to be a reasonable predictor of spirometry declines in various linear regression models and log-linear incidence rate models. A time-weighted average exposure has sometimes been considered biologically plausible for agents (e.g., ammonia, sulfur dioxide) that can cause adverse pulmonary effects from tissue damage to the respiratory tract over a relatively short period of time. It has been postulated that this is one potential mechanism for the α-diketones, such as 2,3-butanedione (diacetyl) and 2,3-pentanedione.

   Should model predictions based on the average exposure metric (e.g., table 5.32), in addition to the cumulative exposure metric (e.g., tables 5.29 and 5.30), be regarded as reasonable estimates of occupational risk from a working lifetime exposure to diacetyl? What are the advantages and disadvantages of such an approach?

6. The quantitative risk assessment section describes the potential presence of a high-risk subpopulation based on observed incidence rate ratio patterns when stratified by cumulative exposure and exposure duration (section 5.3.4). The featured relative risk model includes a term that assumes the presence of a susceptible subpopulation whose risk diminishes exponentially with time.

   Is the small number of available data points sufficiently robust to include a high risk term in the model? Is such a model useful to consider in the development of occupational exposure limits? Please explain whether the excess lifetime risks predicted from models with the high risk term is more credible than those generated from models without the high risk term?

7. Some public comments stated that the occupational epidemiology data sets NIOSH used were not appropriate for quantitative exposure-response and suggested that the agency rely more heavily on the risk assessment published by Toxicology Excellence for Risk Assessment (TERA - Maier et al., 2010). The TERA analysis is based on the animal inhalation study of Morgan et al., 2008 and is discussed in Chapter 6 along with other quantitative methods using the same study data.

   What is the relative adequacy of the animal inhalation and epidemiological data sets for quantifying worker risk associated with exposures to diacetyl? Does the Criteria Document adequately describe the TERA and other animal-based risk approaches? Are the models used to estimate lifetime risk from occupational data or the animal-based risk methodology utilized by the TERA risk assessment more suitable for characterizing diacetyl exposure – response?

Time Frame and Submission of Reviews

Written public comments on the document were accepted until November 18, 2011. Peer reviewers received a copy of all public comments to consider in their technical review. We anticipate completing the peer review process in March 2012. All information received in response to this document is available for public examination and copying at, NIOSH Docket Office, 4676 Columbia Parkway, Room 111, Cincinnati, Ohio 45226. NIOSH includes all comments received without change in the docket, including any personal information provided. A complete electronic docket containing all comments and material related to this document is available on the NIOSH docket at /niosh/docket/archive/docket245.html.