Issues and approaches for ensuring effective communication on acceptable daily exposure (ADE) values applied to pharmaceutical cleaning

Olson, Michael A.; Faria, Ellen C.; Hayes, Eileen P.; Jolly, Robert A.; Barle, Ester Lovšin; Molnar, Lance R.; Naumann, Bruce D.; Pecquet, Alison M.; Shipp, Bryan K.; Sussman, Robert; Weideman, Patricia A.

doi:10.1016/j.yrtph.2016.05.024

Cited by 11 publications

(4 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A key observation regarding differences between methodologies was that “non‐threshold” OELs based on linear extrapolation from TD50 were in a similar range to OELs based on BMDL10 and threshold mechanism (Table 3). In all cases the difference was not greater than factor 10; this is in line with what has been described in the literature (Olson et al, 2016). Dybing, O'Brien, Renwick, and Sanner (2008) and Benford et al (2010) compared the MoE obtained using either the BMDL10 or the T25 as a PoD for several substances.…”

Section: Discussionsupporting

confidence: 92%

“…The process of deriving numerical values for the various sources of uncertainty (also called safety factors, uncertainty factors or modifying factors) is well described in the literature (BAuA, 2022; COC, 2020). Quantitative differences can occur at each individual step of the derivation process, and differences of up to 10‐fold are expected for assessments of the same substance (Olson et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

“…cal values for the various sources of uncertainty (also called safety factors, uncertainty factors or modifying factors) is well described in the literature(BAuA, 2022; COC, 2020). Quantitative differences can occur at each individual step of the derivation process, and differences of up to 10-fold are expected for assessments of the same substance(Olson et al, 2016).Extrapolating from oral experimental animal studies to humans (AF1) is a key step in deriving OELs. A factor of 4 is generally used to extrapolate from rat to human(ECHA, 2012).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Use of the benchmark‐dose (BMD) approach to derive occupational exposure limits (OELs) for genotoxic carcinogens: N‐nitrosamines

Blum

FitzGerald

Wilks

et al. 2023

J of Applied Toxicology

Self Cite

View full text Add to dashboard Cite

N-Nitrosamines are potent carcinogens and considered non-threshold carcinogens in various regulatory domains. However, recent data indicate the existence of a threshold for genotoxicity, which can be adequately demonstrated. This aspect has a critical impact on selecting the methodology that is applied to derive occupational exposure limits (OELs). OELs are used to protect workers potentially exposed to various chemicals by supporting the selection of appropriate control measures and ultimately reducing the risk of occupational cancer. Occupational exposures to nitrosamines occur during manufacturing processes, mainly in the rubber and chemical industry.The present study derives OELs for inhaled N-nitrosamines, employing the benchmark dose (BMD) approach if data are adequate and read-across for nitrosamines without adequate data. Additionally, benchmark dose lower confidence limit (BMDL) is preferred and more suitable point-of-departure (PoD) to calculate human health guidance values, including OEL. The lowest OEL (0.2 μg/m 3 ) was derived for nitrosodiethylamine (NDEA), and nitrosopiperidine (NPIP) (OEL = 0.2 μg/m 3 ), followed by nitrosopyrrolidine (NPYR) (0.4 μg/m 3 ), nitrosodimethylamine (NDMA), nitrosodimethylamine (NMEA), and nitrosodipropylamine (NDPA) (0.5 μg/m 3 ), nitrosomorpholine (NMOR) (OEL = 1 μg/m 3 ), and nitrosodibutylamine (NDBA) (OEL = 2.5 μg/m 3 ).Limits based on "non-threshold" TD50 slope calculation were within a 10-fold range. These proposed OELs do not consider skin absorption of nitrosamines, which is also a possible route of entry into the body, nor oral or other environmental sources. Furthermore, we recommend setting a limit for total nitrosamines based on the occupational exposure scenario and potency of components.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Use of the benchmark‐dose (BMD) approach to derive occupational exposure limits (OELs) for genotoxic carcinogens: N‐nitrosamines

Blum

FitzGerald

Wilks

et al. 2023

J of Applied Toxicology

Self Cite

View full text Add to dashboard Cite

show abstract

“…As toxicity is driven by high local concentrations at the site of contact rather than the systemic dose, it may be overly conservative to extrapolate between routes of administration. 16,19,20 ICH M7 addendum 5 monographs for dimethylcarbamyl chloride and hydrazine illustrate this approach, where careful review of carcinogenicity data reveals more potent carcinogenicity following inhalation administration. Site of contact nasal tumors are observed resulting in a lower TD 50 value compared to oral administration, therefore route-specific PDEs were derived.…”

Section: Determination Of Pdes/ais For Different Routes Of Exposurementioning

confidence: 99%

Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis: Challenges in Expert Decision-Making Exemplified Through a Case Study-Based Workshop

et al. 2021

View full text Add to dashboard Cite

A workshop entitled “Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis” was held at the 2018 Genetic Toxicology Association annual meeting. The objectives of the workshop were to provide an educational forum and use case studies and live multiple-choice polling to establish the degree of similarity/diversity in approach/opinion of the industry experts and other delegates present for some of the more challenging decision points that need to be considered when developing a compound-specific exposure limit (ie, acceptable intake or permissible or permitted daily exposure). Herein we summarize the relevant background and case study information for each decision point topic presented as well as highlight significant polling responses and discussion points. A common observation throughout was the requirement for expert judgment to be applied at each of the decision points presented which often results in different reasoning being applied by the risk assessor when deriving a compound-specific exposure limit. This supports the value of precompetitive cross-industry collaborations to develop compound-specific limits and harmonize the methodology applied, thus reducing the associated uncertainty inherent in the application of isolated expert judgment in this context. An overview of relevant precompetitive cross-industry collaborations working to achieve this goal is described.

show abstract

Occupational Toxicology in the Pharmaceutical Industry

Dolan

Bercu

Graham³

et al. 2023

Patty's Toxicology

View full text Add to dashboard Cite

Much of the activity in the pharmaceutical industry has its origins in the fine chemicals industry of the late nineteenth century. At that time, advances in chemistry and medicine led to the manufacture of pharmacologically active small molecules to produce desirable biological effects to treat diseases and illnesses at relatively low doses. Advances in biology and chemistry in the past quarter century have led to an increase in innovation resulting in a variety of novel modalities, especially recombinant proteins, antibody‐drug conjugates, cell and gene therapies, peptides and polypeptides, oligonucleotides, and vaccines. The roles and responsibilities of occupational toxicologists in the pharmaceutical industry have expanded dramatically in the twenty‐first century, commensurate with the changing regulatory requirements and treatment modalities. The occupational toxicologists' roles have become increasingly multidisciplinary and the scope of their involvement has expanded to encompass diverse aspects of worker safety as well as patient safety, and to include involvement throughout a molecule's development, from early development through postcommercialization.

show abstract

Issues and approaches for ensuring effective communication on acceptable daily exposure (ADE) values applied to pharmaceutical cleaning

Cited by 11 publications

References 16 publications

Use of the benchmark‐dose (BMD) approach to derive occupational exposure limits (OELs) for genotoxic carcinogens: N‐nitrosamines

Use of the benchmark‐dose (BMD) approach to derive occupational exposure limits (OELs) for genotoxic carcinogens: N‐nitrosamines

Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis: Challenges in Expert Decision-Making Exemplified Through a Case Study-Based Workshop

Occupational Toxicology in the Pharmaceutical Industry

Contact Info

Product

Resources

About