Glutaraldehyde (Chemical Abstracts Service [CAS] registry number 111-30-8) has various occupational uses and is associated with adverse health effects including respiratory tract irritation, asthma, and chronic obstructive pulmonary disease. A quantitative risk assessment was conducted to evaluate the likelihood of adverse health effects associated with differing levels of occupational inhalation exposure to glutaraldehyde. Dose-response models were fit to data from a 2-year glutaraldehyde inhalation exposure bioassay conducted by the National Toxicology Program. The benchmark concentration lower bound values of 32 and 44 parts per billion (ppb) were based on bioassay data for female rats and mice that developed squamous epithelium inflammation and respiratory epithelium squamous metaplasia, respectively. These values were used as a point of departure to determine exposure levels relevant to the occupational setting. Extrapolation from rodents to humans assumed a 40-h workweek and an 8-fold uncertainty factor to account for interspecies and interindividual variability. Adjusted benchmark lower bound concentrations of 3 and 4.1 ppb were calculated for inhalation exposure to glutaraldehyde using the endpoints observed in rat and mouse models. Due to the extrapolation parameters used in deriving this result, these findings have applicability for exposure to glutaraldehyde in the occupational setting.

The uncertainty factor concept is integrated into health risk assessments for all aspects of public health practice, including by most organizations that derive occupational exposure limits. The use of uncertainty factors is predicated on the assumption that a sufficient reduction in exposure from those at the boundary for the onset of adverse effects will yield a safe exposure level for at least the great majority of the exposed population, including vulnerable subgroups. There are differences in the application of the uncertainty factor approach among groups that conduct occupational assessments; however, there are common areas of uncertainty which are considered by all or nearly all occupational exposure limit-setting organizations. Five key uncertainties that are often examined include interspecies variability in response when extrapolating from animal studies to humans, response variability in humans, uncertainty in estimating a no-effect level from a dose where effects were observed, extrapolation from shorter duration studies to a full life-time exposure, and other insufficiencies in the overall health effects database indicating that the most sensitive adverse effect may not have been evaluated. In addition, a modifying factor is used by some organizations to account for other remaining uncertainties - typically related to exposure scenarios or accounting for the interplay among the five areas noted above. Consideration of uncertainties in occupational exposure limit derivation is a systematic process whereby the factors applied are not arbitrary, although they are mathematically imprecise. As the scientific basis for uncertainty factor application has improved, default uncertainty factors are now used only in the absence of chemical-specific data, and the trend is to replace them with chemical-specific adjustment factors whenever possible. The increased application of scientific data in the development of uncertainty factors for individual chemicals also has the benefit of increasing the transparency of occupational exposure limit derivation. Improved characterization of the scientific basis for uncertainty factors has led to increasing rigor and transparency in their application as part of the overall occupational exposure limit derivation process.

We read with great interest the recent publication, Evaluation of electronic cigarette liquids and aerosol for the presence of selected inhalation toxins.1 We are particularly grateful to the authors for recognizing the high rate of chronic obstructive pulmonary disease and of bronchiolitis, specifically, in smokers and for measuring the concentrations of diacetyl (DA) and acetyl propionyl (AP, also known as 2,3-pentanedione) in electronic cigarette (e-cigarette) liquids and aerosols. However, we would like to clarify two issues: | The National Institute for Occupational Safety and Health (NIOSH) draft document, Criteria for a Recommended Standard: Occupational Exposure to Diacetyl and 2,3-Pentanedione, proposes recommended exposure limits (RELs) to reduce the risk of respiratory impairment (decreased lung function) and the severe irreversible lung disease, constrictive bronchiolitis obliterans, associated with occupational exposure to these chemicals. As noted by Farsalinos and co-workers in their limitations section, it is not intended to establish “safe” exposure concentrations for consumers or the general public.1 | The exposure comparisons between e-cigarette users and traditional cigarette smokers and workers use values that are not widely accepted.