1,4-D IOXANE IN P ERSONAL C ARE & C LEANING P RODUCTS Steve - - PowerPoint PPT Presentation

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Feb 20, 2023 320 likes •436 views

1,4-D IOXANE IN P ERSONAL C ARE & C LEANING P RODUCTS Steve Risotto June 28, 2019 Previous Conclusions Regarding 1,4-Dioxane Carcinogenicity (~2010-2013) 1,4-DX is readily metabolized at lower doses; metabolic saturation occurs at

SLIDE 1

1,4-DIOXANE IN PERSONAL CARE & CLEANING PRODUCTS

Steve Risotto June 28, 2019

SLIDE 2

Previous Conclusions Regarding 1,4-Dioxane Carcinogenicity (~2010-2013)

1,4-DX is readily metabolized at lower doses;

metabolic saturation occurs at higher doses

Clear evidence that 1,4-DX and metabolites are not

genotoxic

➢ Heath Canada, WHO, and EU: tumors form only after metabolic saturation → non-linear (threshold) mode of action (MOA)

USEPA 2013: there are data supporting a threshold

MOA, but --

Incomplete evidence that cytotoxicity/proliferation

precede tumors

Metabolism not completely characterized
Lack of evidence of a proliferative response

SLIDE 3

Low-Dose Extrapolation (Linear vs Threshold)

SLIDE 4

Key Events in the Regenerative MOA for Carcinogenicity

Source: EPA 2013

SLIDE 5

Content

Reg Tox Pharma 68:387-401 (2014) Liver cell toxicity & proliferation

bserved in reanalysis of National

Cancer Institute (NCI) slides Reg Tox Pharma 88:45-55 (2017) Toxicokinetics characterized Threshold for metabolism identified

Progression to Tumors

SLIDE 6

Characterization

f Metabolism –

fate of 1,4-DX in rodents

Content

Source: Sweeney et al. 2007

SLIDE 7

Characterization of Metabolism – Blood Levels in Female Mice (ACC data)

SLIDE 8

4 0 2 0 0 6 0 0 2 0 0 0 6 0 0 0 1 0 2 0 3 0 4 0

D a y 9 0

1 ,4 D io x a n e (p p m ) H e p a to c e llu la r P ro life ra tio n (% B rd U P o s itiv e C e lls )

Proliferative Response in Female Mice (ACC data)

Gene sets related to proliferation

significantly enriched after 90 days at 6000 ppm

Regulation of Mitotic Cell Cycle
Negative Regulation of Mitotic Cell

Cycle

Mitotic Cell Cycle Checkpoint
Positive Regulation of Mitotic Sister

Chromatid Separation

Mitotic G1-G1 S Phase
M-G1 Transition
Cell Cycle Mitotic

SLIDE 9

Differential Gene Expression (ACC data)

Alterations at the transcriptomic level are minimal

More typical gene expression plot

6000 ppm at 90 days

For reference: example plot from analysis pipeline manual

Alterations at the transcriptomic level were minimal, but with a clear threshold demonstrated

SLIDE 10

Key Events in the Regenerative MOA for Carcinogenicity

Source: EPA 2013