A mechanistic evaluation of the potential for octamethylcyclotetrasiloxane to produce effects via endocrine modes of action

Figures & data

Figure 1. Space filling models of D4, DES, and E2 with the three molecules overlayed in the lower frame.

Table 1. Retention and elimination of 6 h single dose nose-only inhalation exposure to [¹⁴C]D4.

Dose (nose only 6 h)	7 ppm	70 ppm	700 ppm
Retention % of total dose	5.52	5.19	5.37
Tissue levels (µg/g tissue)/t1/2 (h)
Plasma	0.31/58	1.73/57	11.14/89
Fat	1.80/112	32.21/81	284.21^®/131
Liver	1.45/77	13.13/78	171.24/111
Lung	1.61/122	11.00/156	95.72/202
Ovary	1.32/68	18.77/61	151.41/117
Uterus	0.40/127	3.57/129	30.27/102

^®Peak level occurred at 3 h post dose. All others peak occurred at end of dosing.

Table 2. Effects of EE, coumestrol, and D4 on some uterine parameters in immature rats.

Treatment	Concentration	Abs. uterine	RE	Rel. uterine	RE	Uterine
SD rats
Gavage in	mol/kg	wt.↑		wt. ↑		Epithelial
Sesame oil						cell ht. ↑
EE	1.01 × 10^−7	4.69* fold		4.82* fold		2.61* fold
Coumestrol	5.59 × 10^−4	63.6%*#	3.15 × 10^−5	62.1%*#	2.96 × 10^−5
D4	1.69 × 10^−3	23.4%*#	1.83 × 10^−6	27.2%*#	2.23 × 10^−6	61.1%*#
D4	3.37 × 10^−3	43.9%*#	2.35 × 10^−6	51.3%*#	3.16 × 10^−6	95.7%*
EE + D4		55.1%*#	3.68 × 10^−6	63.5%*#	5.21 × 10^−6
F-344 rats
EE	1.01 × 10^−7	4.31* fold		4.36* fold		3.06* fold
D4	1.69 × 10^−3	16.7%*#	1.20 × 10^−6	19.3%*#	1.43 × 10^−6	34.3%*#
D4	3.37 × 10^−3	26.0%*#	3.12 × 10^−6	30.5%*#	5.30 × 10^−6	63.9%*#
EE + D4		63.5%*#	5.21 × 10^−6	70.4%*#	7.13 × 10^−6

Table 3. Effects of EE, genistein, and D4 on some uterine parameters in OVX F-344 rats.

F-344 rats
Treatment	Concentration	Abs. uterine	RE	Abs. uterine	RE
Sc in corn	mol/kg/day	wet wt. ↑		blot. wt. ↑
Oil, 3 days
EE	1.01 × 10^−8	5.72* fold		4.34* fold
Genistein	1.85 × 10^−4	24.0%*#	1.72 × 10^−6	32.6%*#	2.64 × 10^−6
D4, whole body inhal.	2.37 × 10^−4 mol/kg@	33.4%*#	2.14 × 10^−6	44.1%*#	3.36 × 10^−6
700 ppm 16 h/day 3 days
D4 + EE		76.4%*#		79.3%*#
Treatment		Rel. uterine		Rel. uterine
Sc in corn		wet wt. ↑		blot. wt. ↑
Oil, 3 days
EE	1.01 × 10^−8	5.42* fold		3.95* fold
Genistein	1.85 × 10^−4	20.2%*#	1.38 × 10^−6	26.8%*#	2.03 × 10^−6
D4, whole body inhal.	2.37 × 10^−4 mol/kg@	40.0%*#	2.84 × 10^−6	54.6%*#	5.13 × 10^−6
700 ppm 16 h/day 3 days
Treatment		Uterine luminal		Uterine glandular
Sc in corn		Epithelial		Epithelial
Oil, 3 days		cell ht. ↑		cell ht. ↑
EE	1.01 × 10^−8	2.80* fold		1.69* fold
Genistein	1.85 × 10^−4	12.3%*#	7.66 × 10^−7	46.3%*#	4.71 × 10^−6
D4, whole body inhal.	2.37 × 10^−4 mol/kg@	36.2%*#	2.42 × 10^−6	71.4%*#	1.06 × 10^−6
700 ppm 16 h/day 3 days
D4 + EE		93.90%*		93.50%*

^@The measured D4 level in the blotted uterus was at least 2.37 × 10⁻⁴mol/kg. This was measured some time after removal from the animals and there were no precautions taken to prevent evaporative losses of D4 prior to extraction.

Table 4. Effects of EE and D4 on some uterine parameters in OVX SD and F-344 rats.

SD rats
	Concentration	Abs. uterine	Abs. uterine
Treatment	mol/kg/day	wet wt. ↑	blot. wt. ↑
EE, 3 days sc in corn oil	1.01 × 10^−8	5.25* fold	4.06* fold
D4, whole body inhal.	700 ppm	1.02*# fold	1.31*# fold
3 days, 6 h/day
D4 + EE		4.98* fold	3.74* fold
		Rel. uterine	Rel. uterine
		wet wt. ↑	blot. wt. ↑
EE, 3 days sc in corn oil	1.01 × 10^−8	6.07* fold	4.05* fold
D4, whole body inhal.	700 ppm	1.78*# fold	1.28*# fold
3 days, 6 h/day
D4 + EE		5.93* fold	3.85* fold
		Uterine luminal	Uterine glandular
		epithelial	epithelial
		cell ht. ↑	cell ht. ↑
EE, 3 days sc in corn oil	1.01 × 10^−8	2.41* fold	1.62* fold
D4, whole body inhal.	700 ppm	0.24*# fold	0.51*# fold
3 days, 6 h/day
D4 + EE		2.37* fold	1.76* fold
F-344 rats
EE, 3 days sc in corn oil	1.01 × 10^−8	5.69* fold	3.80* fold
D4, whole body inhal.	700 ppm	1.32*# fold	1.16*# fold
3 days, 6 h/day
D4 + EE		6.07* fold	4.04* fold
		Rel. uterine	Rel. uterine
		wet wt. ↑	blot. wt. ↑
EE, 3 days sc in corn oil	1.01 × 10^−8	5.30* fold	5.44* fold
D4, whole body inhal.	700 ppm	1.22*# fold	1.28*# fold
3 days, 6 h/day
D4 + EE		5.66* fold	5.80* fold
		uterine luminal	uterine glandular
		epithelial	epithelial
		cell ht. ↑	cell ht. ↑
EE, 3 days sc in corn oil	1.01 × 10^−8	2.84* fold	1.90* fold
D4, whole body inhal.	700 ppm	0.37*# fold	0.47*# fold
3 days, 6 h/day
D4 + EE		2.77* fold	1.76* fold

Table 5. Effects of EE, 4-hydroxytamoxifen, and D4 on some uterine parameters in OVX F-344 rats.

F-344 rats
Treatment	Concentration	Rel. uterine	RE	Rel. uterine	RE
3 days gavage	mol/kg/day	wet wt. ↑		blot. wt. ↑
in sesame oil
EE	3.37 × 10^−7	3.75* fold		2.64* fold
4-Hydroxytamoxifen	2.58 × 10^−7	0.89*# fold	4.05 × 10^−2	1.06*# fold	8.78 × 10^−2
D4, whole body inhal.	700 ppm	1.13*# fold		1.25*# fold
3 days, 6 h/day
D4, whole body inhal.	700 ppm	2.52*# fold		2.20*# fold
3 days, 16 h/day
		Uterine luminal		Uterine glandular
		epithelial		epithelial
		cell ht. ↑		cell ht. ↑
EE	3.37 × 10^−7	1.68* fold		1.37* fold
4-Hydroxytamoxifen	2.58 × 10^−7	2.47*# fold		1.47* fold
D4, whole body inhal.	700 ppm	<0# fold		0.19*# fold
3 days, 6 h/day
D4, whole body inhal.	700 ppm	2.17*# fold		0.64*# fold
3 days, 16 h/day