Fiber biodurability and biopersistence: historical toxicological perspective of synthetic vitreous fibers (SVFs), the long fiber paradigm, and implications for advanced materials

Figures & data

Figure 1. Mechanisms by which respirable short or long fibers clear from or persist in the lungs and pose a risk of non-carcinogenic and carcinogenic health effects. Respirable long biodurable fibers accumulate and persist in the lungs because of reduced dissolution and breakage and evasion of direct or macrophage-mediated transport out of the lungs. Whereas respirable short fibers or respirable biosoluble fibers undergo dissolution and cellular/acellular transport mechanisms to clear from the lungs (in non-overload conditions) and not pose a risk pulmonary health effects.

Table 1. Summary of in vitro dissolution, in vivo retention and biological responses of SVFs.

Fiber type	Category	Inhalation WT1/2 >20 µm (days)	Intratracheal WT1/2 >20 µm (days)	Kdis @ pH 7.4 (ng/cm^2/h)	Kdis @ pH 4.5 (ng/cm^2/h)	Inhalation Fibrosis	Inhalation Lung Tumors	References
Glass fibers
MMVF10	Glass fiber	37		122.4–300		–	–	Hesterberg et al. 1993, Searl et al. 1999, Maxim et al. 2002, Eastes et al. 1995
MMVF10	Glasswool	44		122.4 (pH 7.0)				Hesterberg et al. 1996, Searl et al. 1999
MMVF10.1	901 Glasswool	14.6				–	–	Maxim et al. 2002
MMVF11	Glass fiber	13		71	0.7	ND	ND	Bernstein et al. 1996
MMVF11	Glasswool	8.7–11	84	71–100		–	–	Hesterberg et al. 1993, Bernstein et al. 1996, Maxim et al. 1999, 2002, 2006, Eastes et al. 1995
CertainTeed glass	MMVF11 Glass fiber	9		100		–	–	Hesterberg, Chase, et al. 1998
JM E-glass	Glass fiber	79		9		+	+	Hesterberg, Chase, et al. 1998
MMVF32	E Glasswool	79	222	6.5		+	+	Davis et al. 1996, Maxim et al. 1999, 2002, 2006
MMVF33	JM 475 glass	49		12		+	+/–	Hesterberg, Chase, et al. 1998
MMVF33	475 Glasswool	48.5	206	53		+	+/–	Davis et al. 1996, McConnell et al. 1999, Maxim et al. 1999, 2002, 2006
JM 901 glass	Glass fiber	15		300		–	–	Hesterberg, Chase, et al. 1998
A	Glass fiber	3.5		129–250	2.4			Bernstein et al. 1996, Hesterberg, Hart, et al. 1998
A	Glasswool	3.5		129	2.4	ND	ND	Bernstein et al. 1996
B	Glass fiber	2.4		320	11.8	ND	ND	Bernstein et al. 1996
B0109	Glasswool	2 − 2.4	7	>500				Hesterberg, Chase, et al. 1998, Maxim et al. 2006
C	New glasswool	4.1 − 4.6	11	309–>500	6.2			Bernstein et al. 1996, Hesterberg, Hart, et al. 1998, Maxim et al. 2002, 2006
C	Glasswool	4.1		309	6.2	ND	ND	Bernstein et al. 1996
M	Glasswool	5	5.7	>500				Hesterberg, Hart, et al. 1998, Maxim et al. 2002, 2006
P	Glasswool	6	11	>500				Hesterberg, Hart, et al. 1998, Maxim et al. 2002, 2006
100/475				9.1 (pH 7.0)		ND	ND	Searl et al. 1999
Rock/SlagWools
MMVF21	Rockwool	78–88.6	190	17–28.9				Maxim et al. 1999, Searl et al. 1999, Maxim et al. 2006
MMVF21	Rockwool (96)	88.6				+	–	McConnell 1994, Maxim et al. 2002
MMVF21	Rockwool (98)	66.5				+	–	McConnell 1994, Maxim et al. 2002
MMVF21	Rockwool	53		28.9 (pH 7.0)				Hesterberg et al. 1996, Searl et al. 1999
MMVF21	Stonewool		196					Bellmann et al. 1995
MMVF21	Stonewool	66.5–88.6		20		+	–	Hesterberg et al. 1996; Hesterberg, Chase, et al. 1998
MMVF21	Rockwool			23	59	NS	NS	Kamstrup et al. 1998
MMVF22	Stonewool	28–140				+	–	Bellmann et al. 2003
MMVF22	Slagwool	5		52.8 (pH 7.0)		ND	ND	Hesterberg et al. 1996, Searl et al. 1999
MMVF22	Slagwool	8.5–9	55	52.8–400		–	–	Hesterberg, Chase, et al. 1998, McConnell 1994, Searl et al. 1999, Maxim et al. 1999, 2002, 2006, Eastes and Hadley 1996
MMVF30	Stonewool		133					Bellmann et al. 1995
MMVF31	Stonewool		123					Bellmann et al. 1995
MMVF34	Stonewool	5.4–6	70	55-59	620	–	–	Hesterberg, Chase, et al. 1998, Kamstrup et al. 2001, Maxim et al. 1999, 2002
F	Stonewool	8.5		96–160	5.9	ND	ND	Bernstein et al. 1996, Hesterberg, Hart, et al. 1998
G	New stonewool	5.0–5.4	12	129–250	4.1			Bernstein et al. 1996, Maxim et al. 1999, Hesterberg, Hart, et al. 1998, Maxim et al. 2002
H	Stonewool	13		169–270	5.5	ND	ND	Bernstein et al. 1996, Hesterberg, Hart, et al. 1998
Insulfrax	AES wool	7		150				Maxim et al. 1999, 2002
Isofrax	AES wool	7		255				Maxim et al. 1999, 2002
L	Stonewool	45		20–23	342	ND	ND	Bernstein et al. 1996; Maxim et al. 1999
O	Stonewool	6	12	>500				Hesterberg, Hart, et al. 1998, Maxim et al. 1999, 2006
RCF
RCF 1	Refractory			4.4 (pH 7.0)		ND	ND	Searl et al. 1999
RCF1	Refractory	53.3–55	266.5	3–7.6		+	+	Hesterberg, Hart, et al. 1998, Maxim et al. 1999, Maxim et al. 2006
RCF1a	Refractory	54.8				+	+	Mast et al. 1995a; Mast et al. 1995b, Maxim et al. 2002
RCF 2	Refractory			3.1 (pH 7.0)		ND	ND	Searl et al. 1999
RCF 4	Refractory			0.5 (pH 7.0)		ND	ND	Searl et al. 1999
Other
SiC1				0.2 (pH 7.0)		ND	ND	Searl et al. 1999
612	Calcia magnesia silica			62.7				Maxim et al. 2006
J (X-607)	Hybrid Fiber	9.8		104	4.3	ND	ND	Bernstein et al. 1996
X607	Hybrid fiber	9.6–9.8	26	104–990		–	–	Hesterberg, Chase, et al. 1998, Maxim et al. 2002, Maxim et al. 2006
Asbestos
Crocidolite	Asbestos	817		<1		+	+	Hesterberg, Chase, et al. 1998
Crocidolite	Asbestos	536				ND	ND	Bernstein et al. 1996
Amosite	Asbestos			0.2 (pH 7)		ND	ND	Searl et al. 1999
Amosite	Asbestos	418		<1		+	+	Hesterberg, Chase, et al. 1998

Note: –: negative; +, positive; +/–: equivocal; ND: no data; NS: not statistically significant.

Table 2. Glass SVF biological effects corresponding to in vitro dissolution at pH 7.4, lung retention following inhalation or intratracheal instillation in Figure 3.

Fiber	Fibrosis	Tumors	Mesothelioma	Comments	Reference
Inhalation
MMVF10	N/A	NS	None	Non-specific inflammatory response; lung burdens higher than occupational exposure (200 f/mg dry tissue)	Hesterberg et al. 1993
MMVF11	N/A	NS	None	Non-specific inflammatory response; lung burdens (6.0E + 05 f/mg/dry tissue) higher than occupational exposure (200 f/mg dry tissue)	Hesterberg et al. 1993
MMVF32 (E-glass)	+	+	N/A	Pathology from Davis et al. 1996 (whole body exposure)	Davis et al. 1996; Hesterberg, Chase, et al. 1998b
MMVF33 (JM475)	Mild up to 13 wks; moderate at 26 wks; marked at 78 and 84 wks	NS	+/– (1/63 hamsters [NS]; none in rats)	18 mo Exposure	McConnell et al. 1999
	+	N/A	1/50 Hamsters (NS)	18 mo Exposure	Hesterberg et al. 1997
901 Glass (MMVF10a)	Mild at all time points	N/A	–	18 mo Exposure	Hesterberg et al. 1997
Intratracheal instillation
MMVF11	Alveolitis noted at 6 and 40 d; no lesions noted up to 720 d	–	ND	Study in sheep	Dufresne et al. 1999

Note: +: positive effects; –: negative effects; +/–: equivocal effects; NS: not statistically significant; N/A: not applicable or evaluated; ND: no data

Table 3. Stone SVF biological effects corresponding to in vitro dissolution at pH 4.5 or 7.4 and lung retention following inhalation in Figure 4.

Fiber	Fibrosis (Wagner Score)	Tumors	Mesothelioma	Comments	Reference
Inhalation
MMVF21	Minimal at 28 mo (4.0)	NS	–	D/R fibrosis; NS tumor incidence; no meso	McConnell 1994
	Minimal at 18 mo (4.0)	N/A	N/A	D/R cellular changes/fibrosis	Kamstrup et al. 1998
	Minimal at 24 mo (4.0)	NS	NS	D/R fibrosis; incidence of non-neoplastic bronchoalveolar hyperplasia in 30 mg/m^3 group was significant	Kamstrup et al. 2001
MMVF22	–	NS	–	2 tumors in 3 mg/m^3 group, none in 16 mg/m^3 group, 3 in 30 mg/m^3 group; NS from control	McConnell 1994
MMVF34	Minimal cellular change at 18 mo (2.8)	NS	NS	Only one dose tested (30 mg/m^3)	Kamstrup et al. 1998
	Mild cellular change at 24 mo (3.2)	NS	NS	Only one dose tested (30 mg/m^3)	Kamstrup et al. 2001

Note: +: positive effects; –: negative effects; +/–: equivocal effects; D/R: dose-response; NS: not statistically significant; N/A: not applicable or evaluated; ND: no data.

Figure 2. Mechanisms of dissolution SVFs depend on the length of the fiber and chemical composition. Irrespective of the composition, short fibers are cleared by direct or macrophage-mediated transport out of the lungs. For long glass SVFs, dissolution and subsequent breakage into shorter fibers occurs in extracellular space and neutral pH 7.4 of the lung lining fluid. In contrast, stone SVFs generally undergo minimal dissolution at neutral pH, but are readily dissolved and broken into shorter fiber segments in the acidic environment (pH 4.5) of the macrophages phagolysosome.

Figure 3. Correlation between in vitro dissolution at pH 7.4 (K_dis, ng/cm²/hr), in vivo clearance (WT_1/2 fibers >20 µm in length) of glass SVFs, and corresponding biological effects (when available, Table 2). The vertical dotted line represent the EU Note Q WT_1/2 threshold (10 days for inhalation, 40 days for intratracheal instillation studies) requirement of exemption of classification for carcinogenicity. Glass SVFs (MMVF32, MMVF33) that demonstrated fibrotic and tumorigenic responses showed K_dis less than 100 ng/cm²/hr and WT_1/2 (inhalation and/or intratracheal instillation) greater than 40–50 days. The confluence of the K_dis (>100 ng/cm²/hr, as illustrated by horizontal dotted line) and WT_1/2 (>40–50 days) thresholds that are not associated with biological effects is represented by the blue shadowed area.

Figure 4. Correlation between in vitro dissolution at pH 4.5 (K_dis, ng/cm²/hr), in vivo clearance (WT_1/2 fibers >20 µm in length) of stone SVFs, and corresponding biological effects (when available, Table 3). The vertical dotted line represent the EU Note Q WT_1/2 threshold (10 days for inhalation, 40 days for intratracheal instillation studies) requirement of exemption of classification for carcinogenicity. Stone SVF (MMVF21) that demonstrated the most significant fibrotic responses (tumorigenic responses were not significant) showed K_dis less than 100 ng/cm²/hr and WT_1/2 (inhalation) greater than 40–50 days. The confluence of the K_dis (>100 ng/cm²/hr, as illustrated by horizontal dotted line) and WT_1/2 (>40–50 days) thresholds that are not associated with biological effects is represented by the blue shadowed area. It is noteworthy that correlations were observed between in vitro K_dis at pH 4.5 (but not pH 7.4) and in vivo WT_1/2 for stone SVFs, however limited data are available for in vitro dissolution at pH 4.5, in vivo clearance, and in vivo health effects (Table 3) for a given stone SVF.

Figure 5. Correlation of fiber dissolution rate (K_dis, calculated) and fiber clearance from the lungs of animals (WT_1/2, weighted half-life) for multiple SVF types show that a K_dis threshold of 100 ng/cm²/hr or greater for glass fibers was consistently associated with an in vivo half-life less than 40 days for fibers >20 µm in length. This is consistent with the Note Q threshold requirements for exemption of fibers for carcinogenicity classification in the EU. Some stone wool fibers were predicted to have a relatively fast K_dis (>100 ng/cm²/hr), but showed a relatively long half-life. While this disparity between calculated K_dis and in vivo clearance of some stone wool fibers needs to be further understood, it may be that actual measured in vitro dissolution of stone wool in buffered solution at pH 4.5 could better align with in vivo biopersistence. It is noteworthy that few SVF types would meet the K_dis 100 ng/cm²/hr and WT_1/2 thresholds if WHO sized fibers were considered.

Table A1. Summary of intraperitoneal injection toxicology studies of SVFs.

Fiber	Exposure	Fiber number and dimensions	Controls	Species	Outcomes	Reference
German glass wool	1x 2 or 10 mg in 2 ml	24, 120 × 10^6 fibers > 5 μm in length; 59% of fibers < 3 μm in length	Chrysotile (6/37 for 2 mg and 25/31 for 25 mg repeat) or 2 mg UICC crocidolite (15/39 tumors) or 50 mg granular corundum (3/37 abdominal tumors)	Rat/hamster	In rats, mesotheliomas and spindle-cell sarcomas were observed at incidences of 1/34, 4/36 for the exposures of 24, 120 × 10^6 German glass fibers. No abdominal tumors in hamsters	Pott et al. 1976; IARC 2002
German glass wool	4x (weekly) 25 mg in 2 ml	1,200 × 10^6 fibers > 5 μm in length; 59% of fibers < 3 μm in length		Rat/hamster	Rats 23/32 for 1200 × 10^6 German glass fibers. No abdominal tumors in hamsters
JM 104 glass fiber	1x for 2 or 10 mg; 2x 25 mg injections (2, 10, or 50 mg total) in 2 ml	Mean fiber dimensions, 0.2 μm x 10 μm		Rat	20/73 (2 mg), 41/77 (10 mg) and 55/77 (50 mg) with mesotheliomas, sarcomas and, occasionally carcinomas observed in rats
JM 112 glass fiber	1x 20 mg in 2 ml	Mean dimensions 1 μm x 30 μm		Rat	14/37 tumors
JM 100 glass fiber (expt 12)	1x 2mg or 10 mg in 2 ml	Median fiber dimensions, 2.4 μm x 0.33 μm	SA crocidolite 0.5 or 2 mg (18/32 low exposure, 28/32 high exposure). Three tumors were noted in rats that received two injections each of either 20 mg Mount St Helen’s volcanic ash or 20 ml saline alone	Wistar or Sprague Dawley rats	Tumor incidence: 2 mg: 21/54; 10 mg: 24/53 animals	Pott et al. 1987; IARC 2002
JM 104E glass fiber	1x 5 mg in 1 ml	Cut and ground for 1 h in an agate mill; median fiber dimensions, 4.8 μm x 0.29 μm			Adult exposure: 44/54; adolescent exposure: 20/45
JM 475 [code 104] glass fiber	1x 0.5 or 2 mg in 1 ml	Median fiber dimensions, 3.2 μm x 0.18 μm			Tumor incidence 0.5 mg: 5/30; 2.0 mg: 8/31
JM 475 glass fiber	2 mg treated w/ HCl in 1 ml	*not stated if differed from above			16/32 with acid-treated glass fiber
ES3 filament	50 and 250 mg/rat in 2 ml	16.5 μm x 3.7 μm			Tumor incidence 6% (50 mg) or 9% (250 mg)
ES5 filament	10, 40 and 250 mg/rat in 2 ml	39 μm × 5.5 μm			Tumor incidence 4% (10mg),11% (40 mg), or 7% (250 mg)
ES7 filament	40 mg/rat in 2 ml	6 μm x 7.4 μm			Tumor incidence 2%
Swedish rock wool	3x 25 mg (75 mg) in 2 ml	Median fiber length, 23 μm; median diameter,1.9 μm			Tumor incidence 45/63 (71.4%)
Swedish rock wool fine fraction	1x 10 mg in 2 ml	Median fiber length, 4.1 μm; diameter, 0.64 μm			Tumor incidence 6/45 (13.3%)
German Slag [Rheinstahl] (expt 3)	2x 20 mg (1x/wk) in 2 ml	Median fiber length of 26 μm and a median fiber diameter of 2.6 μm			Tumor incidence 6/99 (6.1%)
German slag [Zimmermann] (expt 3)	2x 20 mg (1x/wk) in 2 ml	Median fiber length of 14 μm and a median fiber diameter of 1.5 μm			Tumor incidence 2/96 (2%)
Fiberfrax RCF	9 mg x 5 (weekly) 45 mg total in 2 ml	Fiber length, 8.3 μm; fiber diameter, 0.91 μm			Tumor incidence 32/47 (68%)
Manville RCF	15 mg x 5 (weekly) 75 mg total in 2 ml	Fiber length, 6.9 μm; fiber diameter, 1.1 μm			Tumor incidence 12/54 (22%)
Untreated JM104 glass fiber	5 mg	Chopped and ground, 50% were < 4.8 μm in length.	No positive control; Included saline control	Wistar rats	Tumor incidences (estimated from the graph) approximately 80%.
HCl treated JM104 glass fiber		Soaked in 1.4 mol/L HCl at room temperature for 2 or 24 h. Fiber weight loss after 2h: 25%, 24h 33%			Tumor incidences (estimated from the graph) approximately ∼60% (2h) and <10% (24h).
NaOH treated JM104 glass fiber		Soaked in 1.4 mol/L NaOH at room temperature for 24 h			Tumor incidences (estimated from the graph) approximately 80%.
JM 100 glass fibers	25 mg in 0.5 ml	Geometric mean fiber dimensions, 4.7 μm x 0.4 μm; 19% of fibers > 10 μm in length and 0.2–0.6 μm in diameter	20/25 rats injected with 25 mg UICC crocidolite (5% ≥5 μm in length; mean, 3.1 μm), but in neither of the control groups. 40% of hamsters and 80% of rats injected with crocidolite had abdominal mesotheliomas. Saline controls did not have any tumors.	Osborne-Mendel rats	8/25 rats had abdominal mesotheliomas	Smith et al. 1987
Fibrefrax RCF	25 mg in 0.5 ml	GMD of 0.9 μm and a GML of 25 μm but length and diameter distributions and particulate counts for the elutriated material injected were unspecified			19/23 rats had abdominal tumors
Fibrefrax RCF	25 mg in 0.5 ml	GMD of 0.9 μm and a GML of 25 μm but length and diameter distributions and particulate counts for the elutriated material injected were unspecified		Syrian hamsters	Mesotheliomas were found in 2/15 hamsters in the first group and in 5/21 hamsters in the second group (**21/36 and 15/36 from groups 1 and 2 died within 30 d)
JM 104/475	0.5 mg in 1 ml	90% of fibers <8.4 µm long and <0.40 µm diameter; 28% longer than 5 µm	Crocidolite (90% <7.7 µm long and 0.36 µm diameter) or Calidria chrysotile (90% <5.9 µm long and 0.10 µm diameter) or UICC chrysotile (90% <3.6 µm long and 0.18 µm diameter). Tumor incidence: Crocidolite 55%, Calidria chrysotile 6%, UICC chrysotile 84%	Female Wistar rats	17% tumor incidence	Muhle et al. 1987
X7753 Glass Fiber	Single injection 2.5 mg/ml in 2 ml	mean diameter 2.05 µm and mean length 19.4 µm	No positive control	Female Fisher Rats	Retained mass 2 days post injection: 4.08 mg (range 1.83-5.41 mg)	Collier et al. 1994; IARC 2002
X7484 Glass Fiber		Not listed			Retained mass 2 days post injection: 5.16 mg (range 0.21-6.21 mg)
MMVF11 Glass Fiber (CertainTeed)	70 mg (2x 35 mg weekly) or 180 mg (6x 30 mg weekly) in 2 ml	0.4 × 10^9 or 1.0 × 10^9 fibers ; median length 14.6 μm × median diameter 0.77 μm	Crocidolite 0.5 mg (5 injections of 0.1 mg at two week intervals; males and females) or 0.5 mg (females only, 5 injections at weekly intervals. 0.042 x 10^9 fibers; median length of 1.8 μm and median diameter of 0.19 μm. Mesothelioma incidence: 25/32 (78%), 32/48 (67%), 20/39 (51%); Included vehicle controls	Female Rats	Mesothelioma incidence 12/40 (30%) and 16/23 (70%)	Roller et al. 1996
MMVF21 rock wool	60 mg (2x 30 mg weekly) or 180 mg (6x 30 mg weekly) in 2 ml	0.4 × 10^9 or 1.0 × 10^9 fibers; median length of 16.9 μm and median diameter of 1.02 μm		Female Rats	Mesothelioma incidence: 37/38 (97%) and 33/38 (87%)
MMVF22 slag wool	20 mg (1x 20 mg weekly), 50 mg (1 x 50 mg), or 150 mg (3x 50 mg weekly) in 2 ml	0.4 × 10^9,1.0 × 10^9 or 2.9 x 10^9 fibers; median length of 8.7 μm and median diameter of 0.77 μm		Female Rats	Mesothelioma incidence: 4/40 (10%), 8/40 (20%), 18/38 (47%)
R-stone E3	114 mg (4x 28.5 mg) or 256.5 mg (9 x 28.5 mg) in 2 ml	0.4 × 10^9 or 0.9 x 10^9 fibers; median length of 16.9 μm and median diameter of 1.03 μm		Female Rats	Mesothelioma incidence: 0/30 and 4/35 (11%)
M stone	8.5 mg (1x), 25.5 mg (1x), 85 mg (2x 42.5 mg, 2 week interval between) in 2 ml	0.1 × 10^9, 0.3 x 10^9, or 1.0 x 10^9 fibers; median length 10.1 μm and median diameter 0.84 μm		Male and Female Rats	Mesothelioma incidence: 2/32 (6%) and 2/36 (6%) for females and males, 9/32 (28%) and 8/36 (22%) for females and males, and 22/35 (63%) for males
B-20-2.0	6 mg, 18 mg, or 60 mg (2x 30 mg with 2 week interval between) in 2 ml	0.08 × 10^9, 0.24 x 10^9, or 0.8 x 10^9 fibers; median length 7.8 μm and median diameter 0.77 μm		Male and Female Rats	Mesothelioma incidence: 2/32 (6%) females and 15/36 (42%) males, 7/32 (22%) females and 12/34 (35%) males and in 21/35 (60%) males
B-20-0.6	Single injection of 3.5, 8.5 or 25 mg or 75 mg (3 weekly 25 mg) in 2 ml	0.4 × 10^9, 1.0 x 10^9, 3.0 x 10^9, or 9.0 x 10^9 fibers; median length 3.6 μm and median diameter 0.30 μm		Female Rats	Mesothelioma incidence: 12/40 (30%), 17/40 (43%), or 30/40 (75%) and 27/31 (87%)
B-09-0.6 glass wool	100 (2 weekly 50 mg) or 300 mg (6 weekly 50 mg) in 2 ml	2.0 × 10^9 or 6.1 x 10^9 fibers; median length 3.3 μm and median diameter 0.49 μm		Female Rats	Mesothelioma incidence: 1/40 (3%), 4/40 (10%)
B-09-2.0 glass wool	150 (3 weekly 50 mg) or 450 mg (9 weekly 50 mg) in 2 ml	1.1 × 10^9 or 3.2 x 10^9 fibers; median length 10.5 μm and median diameter 1.2 μm		Female Rats	Mesothelioma incidence: 9/40 (23%) and 21/40 (53%)
B-01-0.9 glass wool	125 mg (5 weekly 25 mg), 250 mg (10 weekly 25 mg), 500 mg (20 weekly 25 mg), 1000 mg (40 weekly 25 mg) in 2 ml	2.5 × 10^9, 5.0 × 10^9, 10.0 × 10^9 or 20.0 x 10^9 fibers; median length ∼9.0 μm and median diameter 0.7 μm		Male and Female Rats	Mesothelioma incidence: 3/39 (8%) 125 mg females, 4/37 (11%), 250 mg females and 3/36 (8%) in 500 mg females; 10/48 (21%) 500 mg males and 33/50 (66%) 1000 mg males
753-104 glass fiber	17 or 50 mg in 2 ml	1 x 10^9 3 x 10^9 fibers; median length ∼3.3 μm and median diameter 0.22 μm		Female Rats	Mesothelioma incidence: 30/40 (75%) and 36/40 (90%)
100/475 glass fiber	8.3 mg in 2 ml	9 × 10^6 fibers >20 μm in length (diameter <0.95 μm); 23.7% persistence >20 µm fibers at 12 mo	6.1 mg of amosite asbestos (410 × 10^6 WHO fibers/rat; ∼ 99% of the fibers had diameters below 0.95 μm 21/24 (88%) for amosite treated rats	SPF Wistar rats; 12 month observation	Mesothelioma incidence 8/24 (33%); Kdis pH 7.0: 9.1 ng/cm^2/hr	Miller et al. 1999
MMVF10 glass wool	144 mg in 2 ml	119 × 10^6 fibers >20 μm in length (diameter <0.95 μm); 0.6% persistence >20 µm fibers at 12 mo			Mesothelioma incidence 13/22 (59%); Kdis pH 7.0: 122.4 ng/cm^2/hr
MMVF21 stone wool	183.1 mg in 2 ml	344 × 10^6 fibers >20 μm in length (diameter <0.95 μm); 43% persistence >20 µm fibers at 12 mo			Mesothelioma incidence 19/20 (95%); Kdis pH 7.0: 28.9 ng/cm^2/hr
MMVF22 slag wool	129.6 mg in 2 ml	142 × 10^6 fibers >20 μm in length (diameter <0.95 μm); 1.7% persistence >20 µm fibers at 12 mo			Mesothelioma incidence 13/24 (54.2%); Kdis pH 7.0: 52.8 ng/cm^2/hr
RCF1	110.9 mg in 2 ml	85 × 10^6 fibers >20 μm in length (diameter <0.95 μm); 50.5% persistence >20 µm fibers at 12 mo			Mesothelioma incidence 21/24 (88%); Kdis pH 7.0: 4.4 ng/cm^2/hr
RCF2	188.8 mg in 2 ml	111 × 10^6 fibers >20 μm in length (diameter <0.95 μm); 157.3% persistence >20 µm fibers at 12 mo			Mesothelioma incidence 13/18 (72%); Kdis pH 7.0: 3.1 ng/cm^2/hr
RCF4	90.4 mg in 2 ml	6 × 10^6 fibers >20 μm in length (diameter <0.95 μm); 142.7% persistence >20 µm fibers at 12 mo			Mesothelioma incidence 0/22; Kdis pH 7.0: 0.5 ng/cm^2/hr
100/475 glass fiber		Respirable samples collected from aerosol testing (diameter <3 μm, length >5 μm, aspect ratio >3:1)	Amosite (reported previously in Davis et al. 1996 and Miller et al. 1999)	Male Wister Rats	No carcinomas, 4/38 adenomas (10.5%); no mesotheliomas	Cullen 2000
104E Glass Microfiber	10^9 fibers, (diameter <3 µm, length >5 μm; aspect ratio >3:1) in 2 ml				7/43 carcinomas (16.3%), 3/43 adenomas (7%); 2/43 mesotheliomas (4.7%)
Biosoluble M glass wool	0.5, 2.0, or 5 x 10^9 total fibers (equivalent to 41, 164 and 410 x 10^6 WHO fiber) in 2.5 ml	Stock fibers: GMD 0.42 μm × GML 8.26 μm	Crocidolite Tumor incidence: 0.1 x 10^9 1/51, 1 x 10^9 0/51	Female Wistar Rat	4/50, 0/51 and 2/52 with mesothelioma; T1/2: 5.5 days (>20 µm long), 8.5 days for WHO fibers; Kdis/SiO2: 103.7 ng/cm^2/hr	Grimm et al. 2002
Biosoluble P glass wool	0.5, 2.0, or 5 x 10^9 total fibers (equivalent to 51, 205 and 512 x 10^6 WHO fiber) in 2.5 ml	Stock fibers: GMD 0.43 μm × GML 9.9 μm			1/51, 1/51 and 1/52 with mesothelioma; T1/2: 12 days (>20 µm long), 21 days for WHO fibers; Kdis/SiO2: 610 ng/cm^2/hr
Biosoluble V glass wool	0.5, 2.0, or 5 x 10^9 total fibers (equivalent to 72, 290 and 724 x 10^6 WHO fiber) in 2.5 ml	Stock fibers: GMD 0.8 μm × GML 10.07 μm			2/51, 1/51 and 2/51 with mesothelioma; T1/2: not measured; Kdis/SiO2: 450 ng/cm^2/hr
Biosoluble O stone wool	0.5, 2.0, or 5 x 10^9 total fibers (equivalent to 54, 215 and 536 x 10^6 WHO fiber); 2, 8, or 20 weekly injections in 2.5 ml	Stock fibers: GMD 0.42 μm × GML 11.45 μm			0/51, 1/51 and 1/51 with mesothelioma; T1/2: 12.4 days (>20 µm long), 8.5 days for WHO fibers; Kdis/SiO2: 523 ng/cm^2/hr
B Glass Wool	2.0 or 5 x 10^9 total fibers (equivalent to 216 and 541 x 10^6 WHO fiber); 2,8, or 20 weekly injections in 2.5 ml	Stock fibers: GMD 0.55 μm × GML 9.27 μm			1/51 and 2/53 with mesothelioma; T1/2: 4 days (>20 µm long), 17 days for WHO fibers; Kdis/SiO2: 580 ng/cm^2/hr
HT insulation wool	9 mg: 2.6 x 10^9 total fibers, with 2.1 x 10^9 WHO fibers in 2 ml; 39.6% SiO2; 21.5% Al2O3; 15.4% CaO; 10.7% MgO; 6.4% FeO; 2.0% TiO2	GMD 0.65 μm, GML 10.7 μm; 28% of WHO fraction >20 μm	No positive control; included vehicle controls	Female Wistar rats	No mesotheliomas; 6% of animals had fibrous nodules and 58% had adhesions	Kamstrup et al. 2002
D6 (MMVF21-like)	36 mg: 1.2 x 10^9 total fibers, with 0.9 x 10^9 WHO fibers in 2 ml; 45.9% SiO2; 13.8% Al2O3; 17% CaO; 9.5% MgO; 6.2% FeO; 3.0% TiO3; 2.5% Na2O	GMD 0.8 μm, GML 8.5 μm; 18% of WHO fraction >20 μm			Mesothelioma incidence 32/57 (56%); 88% fibrous nodules and 93% adhesions

Table A2. Summary of intrapleural injection toxicology studies of SVFs.

Fiber	Exposure	Fiber number and dimensions	Controls	Species	Outcomes	Reference
Glass borosilicate	1x 20 mg in 0.4 ml	30% 1.5–2.5 µm diameter, max 7 µm; 60% >20 µm length	Two samples of chrysotile: tumors 23/36 and 21/32 (64–65%)	SPF rat; survival ranged from 568 (chrysotile) to 774 (glass fibers)	No tumor induction	Wagner et al. 1973
Glass borosilicate powder		Borosilicate max 8 µm diameter			1 mesothelioma (2.8%)
Suspended solids of RCF/ball milled		No dimensions given			9.7% pleural mesothelioma
2 types of borosilicate glass fibers each prepared by hand grinding or mechanical mortar and pestle	1x 10 mg in 0.5 ml	Separated samples with avg diameters between 0.05 and 3.5 µm into samples with lengths of 100+ µm and <20 µm long	Chrysotile and crocidolite, no exposure listed; 2/150 chrysotile and crocidolite animals had pleural tumors	Mouse; 18 month survival (37/52)	No pleural tumors in glass treated animals	Davis 1976
Fine JM100 glass fiber	20 mg in 0.4 ml	99% <0.5 μm diameter with a median diameter of 0.12 μm; 2% >20 μm in length with a median length of 1.7 μm	No positive control; Included vehicle control	Wistar rats; survival until natural death	4/32 (12%) mesotheliomas	Wagner et al. 1976
Coarse JM110 glass fiber	20 mg in 0.4 ml	17% of fibers <1 μm in diameter with a median diameter of 1.8 μm; 10% >50 μm in length and a median length of 22 μm			No pleural tumors were noted with the coarser US JM 110 glass fiber
Resin coated or uncoated glass fibers (17 types)	40 mg in 1.5 ml 10% gelatin (vehicle) on coarse fiber glass pledgets	Samples with avg diameters between 0.06 and 25 µm	No positive control	Osborne-Mendel rats; thoracic implantation; 2 year observation	Pleural mesothelioma in animals that survived for more than 52 weeks varied from 0/28 to 20/29, dependent upon fiber size. When two of the glass fiber preparations (diameter, >0.25 μm) were leached to remove all elements except silicon dioxide, the incidences of pleural mesotheliomas were 2/28 and 4/25	Stanton 1977; IARC 2002
Fine fraction JM104 glass fiber	20 mg in 2 ml	mean length, 5.89 μm; mean diameter, 0.229 μm	20 mg chrysotile A (mean dimensions, 3.21 μm x 0.063 μm) or crocidolite (mean dimensions, 3.14 μm x 0.148 μm), or varied concentrations of acid to leach chrysotile/crocidolite. Tumor incidence with untreated chrysotile was 15/33 and 21/39 with untreated crocidolite. Acid-leaching reduced tumor incidence (loss of 89.1% MgO resulted in no tumors/mesothliomas)	Sprague Dawley rats	JM104 glass fiber had a mesothelioma incidence of 6/45 (13%)	Monchaux et al. 1981
English glass wool dust	20 mg	Resin coated (70% fibers ≤5 μm in length; 85% ≤1 μm in diameter), or without resin coating (57% ≤5 μm in length; 85% ≤1 μm in diameter)	20 mg chrysotile (fibers longer than 5 µm: 196 x 10^8; particles > 1 µm: 8.8 x 10^8). 6/48 mesotheliomas (12.5%); Included vehicle control	Sprague Dawley rats	One mesothelioma (unclear if it this occurred in the coated or uncoated group)	Wagner et al. 1984
Swedish rock wool		Resin coated (70% fibres ≤5 μm in length; 77% ≤1 μm in diameter), Swedish rock (stone) wool after removal of resin (70% ≤5 μm in length; 81.5% ≤1 μm in diameter)			Mesotheliomas- 3/48 with resin; 2/48 without resin
German slag wool		Resin coated (67% ≤5 μm in length; 70% ≤1 μm in diameter), without resin (80% ≤5 μm in length; 2% ≤1 μm in diameter			No mesotheliomas
JM 100 glass fiber		88% ≤5 μm in length; 98.5% ≤1 μm in diameter			Mesotheliomas 4/48 (8.3%)
Saffil RCF	20 mg in 2 ml	Diameter ≤ 3 μm, 86%; length ³ 10 μm, 92%	20 mg chrysotile: 19/48 (40% tumor incidence, excluding mammary and pituitary; 7/48 (14.5%) pleural mesotheliomas. Included vehicle control – High background tumor incidence: saline control animals 10/48 (21%) (excluding pituitary and mammary tumors); no mesothelioma	Albino Wistar rats	No mesothelioma ; 10/48 (21%) tumors (excluding pituitary and mammary)	Pigott & Ishmael 1992
Aged (1200C) Saffil RCF		Diameter ≤ 3 μm, 82%; length ≥10 μm, 99.7%			No mesothelioma; 7/48 (15%) tumors (excluding pituitary and mammary)
RCF suspended solids of fiber A(kaolin)		Diameter ≤ 3 μm, 66%; length ≥10 μm, 80%			No mesothelioma; 4/46 (9%) tumors (excluding pituitary and mammary)
RCF suspended solids of fiber B (alumina/silica)		Diameter ≤ 3 μm, 92%; length ≥10 μm, 46%			3/48 (6%) mesothelioma; 15/48 (31%) tumors (excluding pituitary and mammary)
RCF- aluminosilicate fibers (High Duty grade), vitrified	20 mg in 0.4 ml	52–56 wt- % alumina and 44-48 wt-% silica; arithmetic mean fiber diameter is 2-3 µm; length not listed. 19-24 animals/group. Ground to a fine powder using a mortar and pestle	No positive control; Included vehicle control	Wistar-Porton rats	No mesothelioma tumor induction; four pleural hyperplasias	Carthew et al. 1995
RCF- aluminosilicate fibers (High Duty grade), devitrified 2 1200C					No mesothelioma tumor induction; six pleural hyperplasias
RCF- aluminosilicate fibers (High Duty grade), devitrified at 1400C					No mesothelioma tumor induction; two pleural hyperplasias

Table A3. Summary of intratracheal instillation toxicology studies of SVFs.

Fiber	Fiber prep	Binder/coating	Experimental design	Fiber number and dimensions	Controls	Outcomes	Reference
Glass Fibers	Ball Milled	Uncoated	Rats/Hamsters 3 x 3.5 mg in 1 ml	Average diameter at 0.5 µm and the average length of 10 µm with a range of 5-20 µm	Saline controls	Polyploid masses of inflammatory tissue in smaller bronchial divisions (4 days post exposure); no evidence of these masses at 12 mo. Alveoli around respiratory bronchioles & alveolar ducts contained dust filled macrophages	Gross et al. 1970
			Rats 10 x 3.5 mg in 1 ml
		Phenol-formaldehyde coated	Hamsters: 1 x 3.5 mg in 1 ml
			Hamsters: 2 x 1.75 mg in 1 ml
			Hamsters: 3 x 3.5 mg in 1 ml
			Rats, 3 x 3.5 mg in 1 ml
			Rats, 10 x 3.5 mg in 1 ml
		Starch Coated	Hamsters: 3 x 3.5 mg in 1 ml
			Rats, 3 x 3.5 mg in 1 ml
			Rats, 10 x 3.5 mg in 1 ml
JM100 Glass Fibers (no binder)	Wetted with ethanol then placed in a plug-packing mold assembly (dried overnight); aerosolized through a Timbrell generator	Not listed	Osborne-Mendel rats & Syrian Golden hamsters 1x/week for 5 weeks; 2 mg/instillation (10 mg) in 0.2 ml	Mean diameter 0.45 µm, GMD 0.4 µm and geometric mean length [GML] 4.7 µm; 94% of fibers were ≤20 µm	UICC crocidolite 74% of hamsters (13/20 benign, 7/20 malignant) and 8% (2 malignant) of rats had primary tumors; both hamsters and rats developed significant fibrosis	No tumors noted; 14% of rats had bronchoalveolar metaplasia; 32% of rats had fibrosis	Smith et al. 1987
RCF Carborundum Fibrefrax (no binder)				Mean diameter 1.8 µm with a GMD of 0.9 µm and GML 25 µm; approximately 86% of fibers had diameters <2.0 µm with 83% of fibers >10 µm long		No tumors noted; 27% of rats had bronchoalveolar metaplasia; 16% of hamsters and 9% of rats had fibrosis
JM104/475 Glass Fiber	Cut with scissors, ground in knife mill for 30 min	Not listed	Wistar rats, 20 weekly instillations of 0.5 mg in 0.3 ml (10 mg total dose)	50% length <3.2 µm and width <0.18 µm	South African crocidolite; median dimensions of fibers, (20 x 0.5 mg weekly) 2.1 μm x 0.2 μm; 15/35 rats developed lung tumors of which 11 were carcinomas and four had mixed tumors	1/34 adenoma, 2/34 adenocarcinoma, 2/34 squamous cell carcinoma total incidence 14.7%	Pott et al. 1987
Rock Wool	Not listed	Not listed	Syrian hamsters; 2 mg/dose 1 x/wk in 0.2 ml for 5 weeks (10 mg total dose); animals sacrificed 2 yrs after first instillation	6.1 µm x 296 µm	Included neg vehicle control; Positive control included amosite (1.05 µm x 15.5 µm) and crocidolite 0.88 µm x 17.4 µm), which resulted in 2/20 tumors (lung adenoma, mesothelioma) and 0/20 tumors, respectively.	No tumor induction; inflammation, fibrosis, and pleural thickening noted	Adachi et al. 1991; 1992
Glass Fiber				0.65 µm x 16.8 µm		Inflammation and pleural thickening; 1 squamous cell carcinoma (lung) and 1 adrenal gland neuroblastoma (2/20)
Potassium Titanate				0.36 µm x 7.17 µm		Inflammation and pleural thickening; no tumor induction
Calcium Sulfate				1.0 µm x 17.8 µm		Inflammation; 3/20 tumors: found in rib, heart or kidney
Basic Magnesium Sulfate				0.45 µm x 22.4 µm		Pleural thickening; 9/20 tumors of which 1 was unspecified lung and 2 were mesotheliomas
Metaphos-phate				2.38 µm x 64.1 µm		Inflammation; 5/20 tumors with 1 mesothelioma
X607 GlassFiber	Sized	Not listed	Wistar rats; single instillation 2 mg in 0.3 ml; serial sacrifices up to and including 24 mo	4 or 8 x 10^6 fibers; length >5 μm and a diameter <2 μm (aspect ratio >5:1; size distribution not given	No positive or negative controls	T1/2= all fibers 47 days (range of 41–54 days); WHO fibers 46 days (41-54 days)	Muhle et al. 1994
MMVF21 Rock Wool	Not listed	Not listed	Female Wistar rats, 2 mg single exposure in 0.3 ml. 5 rats/group sacrificed at 2 d, 2 wks, 1, 3, 6, or 12 mo	400 fibers of stock samples; critical fibers/ng (L > 5 µm, D <2 µm, L/D > 5/1): 29. 90% of fibers <15.3 µm long, <1.21 µm diameter	UICC Crocidolite Long (increased fraction of long fibers); 0.1 mg/0.3 ml saline. Groups sacrificed at 2d, or 6, 12 mo. Lung dose: Total fibers: 2d: 197.5 x10^6/lung, 6 mo: 99.9 x 10^6/lung, 12 mo: 135.2 x 10^6/lung. Mean T1/2: 695 d (L > 5 µm, D < 3 µm)	Total fibers: 2d: 124.1 x 10^6/lung, 1 mo: 111.9 x 10^6/lung, 3 mo: 92 x 10^6/lung, 6 mo: 45.2 x 10^6/lung, 12 mo: 50.8 x 10^6/lung; Mean T1/2 WHO fibers (L > 5 µm, D < 3 µm): 291d	Bellmann et al. 1994
HT Stone Wool				400 fibers of stock samples; critical fibers/ng (L > 5 µm, D <2 µm, L/D > 5/1): 17. 90% of fibers <27.9 µm long, <1.62 µm diameter		Total fibers: 2d: 40.2 x 10^6/lung, 1 mo: 30.8 x 10^6/lung, 3 mo: 22.7 x 10^6/lung, 6 mo: 9.4 x 10^6/lung, 12 mo: 4.5 x 10^6/lung; Mean T1/2 WHO fibers (L > 5 µm, D < 3 µm): 98d
M-104/475 Glass	Not listed	Not listed	0.8 x 10^9 fibers (10 instillations of 0.5 mg each) or 1.6 x 10^9 fibers (20 instillations of 0.5 mg each); 5 or 10 mg dose	length >5 μm and a diameter <2 μm (aspect ratio > 5:1; size distribution not given	Tremolite: 2.5 mg (5 doses of 0.5 mg each) or 7.5 mg (15 doses of 0.5 mg each); total number of tremolite fibers in the low dose was 70 × 10^6 and 300 × 10^6 fibers were in the high dose; (length, >5 μm; diameter, <2 μm; aspect ratio, >5:1). Animals had 6/38 non-lung tumors in the low dose group and 4/37 in the high dose group	5 mg: 8/55 and 10 mg: 4/38 with "other" tumors" (includes fibrosarcomas, lymphosarcomas, mesotheliomas and lung metastases	Pott et al. 1994
Rock wool			4 x 10^6 fibers (10 instillations of 0.5 mg each) or 20 weekly doses of 0.5 mg each; 4 or 8 x 10^6 fibers; 5 or 10 mg dose			5 mg: 5/59 and 10 mg: 4/40 with "other" tumors" (includes fibrosarcomas, lymphosarcomas, mesotheliomas and lung metastases)
MMVF21 Rock Wool	Size fractions	Not listed	Female wistar rats, single dose (2 mg in 0.3 ml). 5 rats/group sacrificed at 2d, 2wks, 1,3,6, or 12 mo	Stock fibers: 90% of fibers 15.3 µm long, 1.21 µm diameter	Studied in Bellmann et al. 1994	Total fibers: 2d: 103.9 x 10^6/lung, 1 mo: 93.7 x 10^6/lung, 3 mo: 80.8 x 10^6/lung, 6 mo: 40.9 x 10^6/lung, 12 mo: 46.7 x 10^6/lung, 18 mo: 32.1 x 10^6/lung; Mean T1/2: Fibers >20 µm long: 196 d; WHO fibers 326 d	Bellman et al. 1995
MMVF30 Rock Wool				Stock fibers: 90% of fibers 18.3 µm long, 1.46 µm diameter		Total fibers: 2d: 49.8 x 10^6/lung, 1 mo: 44 x 10^6/lung, 3 mo: 38.9 x 10^6/lung, 6 mo: 31.8 x 10^6/lung, 12 mo: 24.2 x 10^6/lung, 18 mo: 19.4 x 10^6/lung; Mean T1/2 Fibers >20 µm long: 133 d; WHO fibers 357 d
MMVF31 Rock Wool				Stock fibers: 90% of fibers 23.1 µm long, 1.59 µm diameter		Total fibers: 2d: 55 x 10^6/lung, 1 mo: 43.3 x 10^6/lung, 3 mo: 36.9 x 10^6/lung, 6 mo: 21.7 x 10^6/lung, 12 mo: 16.1 x 10^6/lung, 18 mo: 16 x 10^6/lung; Mean T1/2 Fibers >20 µm long: 123 d; WHO fibers 257 d
100/475 Glass Fiber	Size Selected	Not listed	Male Wistar rats; single instillation (0.5 ml of 2 mg/ml) into the deep lung using a blunt cannula. Lung burden evaluated at 3d and 12 mo	Recovered fibers: All fibers: mean diameter 0.2 µm (3 d) and 0.27 µm (12 mo). Fibers longer than 20 µm: 0.79 µm (3 d) and 0.51 µm (12 mo). Majority of fibers recovered were 0.4-5 µm long	Recovered fibers: All fibers: mean diameter 0.31 µm (3 d) and 0.35 µm (12 mo). Fibers longer than 20 µm: 0.5 µm (3 d) and 0.52 µm (12 mo). Majority of fibers recovered were 0.4-5 µm long. Fibers longer than 0.4 µm: 3d: 563 x 10^6 fibers/lung 12 mo: 39.2 x 10^6 fibers/lung; 7% of 3d remaining	Fibers longer than 0.4 µm: 3 d: 2,466 x 10^6 fibers/lung 12 mo: 255 x 10^6 fibers/lung; 10% of 3 d remaining. Kdis: 9.1 ng/cm^2/hr; Silica leached in NaOxalate pH4.6: 6.3% pH 7: 5.9%	Searl et al. 1999
MMVF10 Glass Wool				Recovered fibers: All fibers: mean diameter 1.39 µm (3 d) and 0.63 µm (12 mo). Fibers longer than 20 µm: 1.62 µm (3 d) and 0.95 µm (12 mo). Lengths were distributed across ranges with more fibers >20 µm long		Fibers longer than 0.4 µm: 3 d: 4.15 x 10^6 fibers/lung 12 mo: 0.64 x 10^6 fibers/lung; 15% of 3 d remaining. Kdis: 122.4 ng/cm^2/hr; Silica leached in NaOxalate pH 4.6: 30.7% pH 7: 15.3%
MMVF21 Rock Wool				Recovered fibers: All fibers: mean diameter 0.97 µm (3 d) and 1.14 µm (12 mo). Fibers longer than 20 µm: 1.13 µm (3 d) and 1.41 µm (12 mo). Lengths were distributed across ranges with more fibers >20 µm long		Fibers longer than 0.4 µm: 3 d: 6.1 x 10^6 fibers/lung 12 mo: 2.27 x 10^6 fibers/lung; 37% of 3 d remaining. Kdis: 28.9 ng/cm^2/hr; Silica leached in NaOxalate pH 4.6: 1.6% pH 7: 2.8%
MMVF22 Slag Wool				Recovered fibers: All fibers: mean diameter 0.89 µm (3 d) and 0.47 µm (12 mo). Fibers longer than 20 µm: 1.11 µm (3 d) and 1.08 µm (12 mo). Lengths were distributed across ranges.		Fibers longer than 0.4 µm: 3 d: 7.09 x 10^6 fibers/lung 12 mo: 1.5x 10^6 fibers/lung 21% of 3 d remaining. Kdis: 52.8 ng/cm^2/hr; Silica leached in NaOxalate pH 4.6: 51.3% pH 7: 52.7% *solution saturated at 14 d, data extrapolated
RCF1				Recovered fibers: All fibers: mean diameter 0.95 µm (3 d) and 0.93 µm (12 mo). Fibers longer than 20 µm: 1.18 µm (3 d) and 1.1 µm (12 mo). Lengths were distributed across ranges.		Fibers longer than 0.4 µm: 3 d: 7.39 x 10^6 fibers/lung 12 mo: 4.53 x 10^6 fibers/lung; 61% of 3 d remaining. Kdis: 4.4 ng/cm^2/hr; Silica leached in NaOxalate pH 4.6: 0.3% pH 7: 0.4%
RCF2				Recovered fibers: All fibers: mean diameter 1.11 µm (3 d) and 1.3 µm (12 mo). Fibers longer than 20 µm: 1.64 µm (3 d) and 1.46 µm (12 mo). Lengths were distributed across ranges.		Fibers longer than 0.4 µm: 3 d: 3.81 x 10^6 fibers/lung 12 mo: 2.62 x 10^6 fibers/lung; 69% of 3 d remaining. Kdis: 3.1 ng/cm^2/hr; Silica leached in NaOxalate pH 4.6: 0.2% pH 7: 0.4%
RCF4 (heat-treated RCF1)				Recovered fibers: All fibers: mean diameter 1.21 µm (3 d) and 1.29 µm (12 mo). Fibers longer than 20 µm: 2.1 µm (3 d) and 1.96 µm (12 mo). Majority of fibers recovered were <10 µm long.		Fibers longer than 0.4 µm: 3 d: 8.9 x 10^6 fibers/lung 12 mo: 7.08 x 10^6 fibers/lung; 80% of 3 d remaining. Kdis: 0.5 ng/cm^2/hr; Silica leached in NaOxalate pH 4.6: 0.1% pH 7: 0.2%
MMVF11 Glass Fiber	Not listed	Not listed	Sheep, single instillation (100 mg/animal). 10/group removed for analysis at days 6, 40, 60, 180, 360, and 730	Not listed	Crocidolite (100 mg/100 ml); All lengths: T1/2 (fast) 69-90 d; T1/2 (slow) 501 d; Fibers ≤5 µm: T1/2 (fast) 93-101 d; T1/2 (slow) 340 d. Pathology: Day 6, 40, 60: peribronchiolar inflammatory lesions, few fibers. Day 180: peribronchiolar inflammatory lesions or without lesions, few fibers. Day 360: peribronchiolar inflammatory lesions, beginning of fibrosis, notable amt of fibers. Day 720: no significant lesions, interstitial pneumonitis, few fibers	Days 6, 40: alveolitis, no lesions, none/few fibers. Days 60, 180, 360, 720: no lesions, none/few fibers. All lengths: T1/2 (fast) 33-42 d; T1/2 (slow) 462 d; Fibers >5 µm: T1/2 (fast) 31-35 d; T1/2 (slow) 572 d	Dufresne et al. 1999
MMVF21 Rock Wool						Day 6: alveolitis, no lesions, few fibers. Day 40: alveolitis, no lesions, notable amount of fiber. Days 60, 180: alveolitis, no lesions, few fibers. Day 360: alveolitis, no lesions, notable amount of fibers. Day 720: alveolitis, no lesions, few fibers. All lengths: T1/2 (fast) 45 d; T1/2 (slow) 433 d; Fibers >5 µm: T1/2 (fast) 45 d; T1/2 (slow) 517 d
RCF-1						Day 6: light alveolitis, few fibers. Day 40: alveolitis, notable amt of fibers. Days 60, 180: alveolitis, few fibers. Day 360: no lesions very few fibers. Day 720: no lesions, very few fibers. All lengths: T1/2 (fast) 67-156 d; T1/2 (slow) 537 d; Fibers >5 µm: T1/2 (fast) 61-157 d; T1/2 (slow) 254 d
MMVF10a Glass Fiber	RCC sourced, details not provided	Not listed	Male Syrian Golden hamsters, aerosol delivered (2 mg/ml) through a tracheal cannula for 5-12 minutes until a sufficient number of fibers for microscopic analysis were delivered. The number of inhaled and exhaled fibers were measured by pneumotachography and laserlight scattering photometry.	Avg length of 200 fibers measured by light microscopy: 16 µm (range 1-66 µm); avg diameter 1.1 µm (range 0.6-1.7); ratio 15.6 (range 1.1-64)	No positive or negative controls	Fibers on the surfaces of conducting airways/alveoli. 89% of the fibers were totally and 11% partially covered by lining-layer material in airways. 32% of the fibers were totally submersed; others touched the alveolar wall, stuck at one end, bridging the airspace in alveoli. Studies in a surface balance showed that fibers were immersed into the aqueous subphase by approximately 50% at film surface tensions of 20–25 mJ/m^2 and were immersed at approximately 10 mJ/m^2. Fibers were also phagocytosed by macrophages. Substantial number of particle profiles within alveolar blood capillaries.	Geiser et al. 2003
Rock Wool	Not listed	Not listed	Male Fischer rats, 2 mg (1x in 0.2 ml) or 2 mg (2 mg once/wk for 4 wks); 2 or 8 mg for 4 or 16 weeks	Not listed	No positive control; Included vehicle control	SOD activity significantly decreased in BALF (8 mg 4w). Ascorbic Acid significantly increased in lung tissue (8 mg 4 wks)	Kovacikova et al. 2005
MMVF10 Glass Wool
RCF	Not listed	Not listed	Male Wistar rats- 2 x 2 mg in 0.4 ml (once weekly) 6 mo recovery; 4 mg total dose	All fibers listed as > 20 µm long; only 18% ≤1 µm in diameter	No positive control; Included vehicle control	Statistically significant increase in proportion of lymphocytes and neutrophils, % immature alveolar macrophages (AM) and phagocytic activity of AM; Statistically significant decrease in viability of AM and proportion of AM as a % of total in comparison with the control group.	Hurbankov et al. 2005
Rock wool RW1	Not listed	Not listed	Male wild-type or homozygous -lacI transgenic F344 Rats instilled either 1x (1 or 2 mg) or 2 mg 1x weekly for 4 weeks. 10 mg/ml stock suspension. 1, 2, or 8 mg total dose	1 mg contained 1,700 fibers; mean 1.8 µm x 16.5 µm; median 3 µm x 23 µm; 85% of fibers <5 µm or diameter <60 µm long	No positive control; Included vehicle control	Significant increase in mutation frequency after 16 wk exposure; DNA strand breaks were increased in alveolar macrophages and lung epithelial cells; Neutrophils in BALF at greater level than MMVF10 at 16 weeks post-exposure; no increase in oxidative markers. T1/2=∼3-4 mo	Topinka et al. 2005
MMVF10 Glass Wool				1 mg contained 8,300 fibers longer than 5 µm and 3,300 fibers >20 µm long; mean 1.31 µm x 22.6 µm; median 2 µm x 26 µm; 85% of fibers <3 µm diameter or <66 µm long		No change in mutation frequency; DNA strand breaks were increased in alveolar macrophages and lung epithelial cells; lower levels of neutrophils in BALF compared to RW1 at 16 weeks post-exposure; No increase in oxidative markers. T1/2= ∼10-11 mo; W-T1/2= ∼37 days (from Hesterberg et al. 1998)

Table A4. Summary of whole-body inhalation toxicology studies of SVFs.

Fiber	Fiber prep & binder/coating	Exposure	Fiber dimensions	Exposure/respirable fiber conc	Controls	Outcomes	Reference
Glass Fibers	Ball milled; Uncoated	135 mg/m^3	Averaging 1 µm in diameter of fiber lengths of predominately 50 µm or less; 70-76% fibrous and 24-30% non-fibrous particles	Rats, hamsters; 5 hr/d, 5 d/wk for 24 months with interim sacrifices at 6 and 12 mo. Not determined (average concentration in dust chamber estimated at 100 mg/m^3)	Fresh air controls	No lesions noted in either rats or hamsters; alveoli around respiratory bronchioles & alveolar ducts contained dust filled macrophages	Gross et al. 1970
	Ball milled; Phenol-Formaldehyde	106 mg/m^3
	Ball milled; Starch Binder	113 mg/m^3
Glass Fiber	Ball Milled	0.7 × 10^6/L	Ball-milled diameters ranged from 0.2-6.5 µm; ∼80% of lengths ≤3 µm	Sprague Dawley rats, hamsters, guinea pigs 5 hr/d, 5 d/wk for 3 months. 0.424 mg/L (6.54 x 10^6 total fibers/L air; 0.73 x 10^6 fibers/L >5 µm long)	Amosite 0.30 mg/L with 3.1 x 10^6/L >5 µm; 3100 fibres/cm^3 > 5 μm in length; 38% with length < 3 μm or ∼1178 WHO fibers/cm^3 3/12 animals with tumors; Fresh air controls	Hamsters 0/61; Rats 2/61; guinea pigs 2/61 (bronchoalveolar adenomas)	Lee et al. 1981; IARC 2002
Fybex (Potassium Octanitate)	–	2.9 × 10^6/L	6.7 x 0.2 µm	Sprague Dawley rats, hamsters, guinea pigs 5 hr/d, 5 d/wk for 3 months. Expt 1: 0.079 mg/L; (Expt 2: 0.039, 0.082, or 0.37 mg/L; Expt 1: 8.53 x 10^6 total fibers/L; 41.76 x 10^6 fibers/L >5 µm long; Expt 2: 6.72, 36.10, or 101.5 x 10^6 total fibers/L air; 2.94, 13.49, or 41.76 x 10^6 fibers/L >5 µm long)		Expt 1: Hamsters 1/64 (pleural mesothelioma); Rats 1/64 (bronchoalveolar adenoma); guinea pigs 0/64. Expt 2: rats 3/63 and 1/58 in mid and high exposure, guinea pigs no tumors, hamsters 1/63 mesothelioma in the mid exposure group and 1/63 pleural mesothelioma and 2/58 [one with mesothelioma, one bronchoalveolar adenoma)
PKT (pigment potassium titanate)	–	2.0 × 10^6/L	4.2 x 0.2 µm	Sprague Dawley rats, hamsters, guinea pigs 5 hr/d, 5 d/wk for 3 months. 0.073 mg/L (6.53 x 10^6 total fibers/L air; 2.00 x 10^6 fibers/L >5 µm long)		Hamsters 0/64; Rats 0/64; guinea pigs 0/64
SG Glass Wool	Ring vibro-grinding mill; Timbrell Dust Generator; Resin Free	5 mg/m^3	68.7% of fibers with diameters < 1 µm, 41.5% of fibers ≤ 10 µm in length (65.5% respirable)	Wistar rats, 5 hr/d, 5 d/wk for 12 or 24 months. 48 WHO fibers/cm^3 (avg respirable dust concentrations at 12 months 5.20 mg/m^3; 4.96 mg/m^3 at 24 mo)	Canadian chrysotile (714-7D; 89.9% <5 µm in length; 93.9% respirable fibers <5 μm in length; 5901 WHO fibers/cm^3). Measured in respirable dust chambers at 12 mo: 4.99 mg/m^3 or 5.20 mg/m^3 at 24 mo; 5/24 males and 4/23 females with pulmonary tumors. Lowest lung retention by mass of 0.70 (12 mo) and 1.66 (24 mo) mg/g dry lung weight (83% clearance 16 mo post 12 mo exposure)	Lung: 12 and 24 mo: 2.12 and 3.19 mg/g dry tissue (67% clearance 16 mo post 12 mo exposure). 1/23 males and 0/22 females had pulmonary tumors; 3/22 females with digestive tumors	Le Bouffant et al. 1987
SG Rock Wool	Carded then ring vibro-grinding mill; Timbrell Dust Generator; Resin Free		22.7% <1 μm in diameter, 39.9% of fibers ≤10 μm in length (56.6% respirable)	Wistar rats, 5 hr/d, 5 d/wk for 12 or 24 months. 11 WHO fibers/cm^3 (avg respirable dust concentrations at 12 months 4.14 mg/m^3; 5.37 mg/m^3 at 24 mo)		Lung: 12 and 24 mo: 1.03 and 2.57 mg/g dry tissue (84% clearance 16 mo post 12 mo exposure). 0/23 males and 0/22 females with pulmonary tumors; 1/24 digestive tumor (male) **Rock wool had a high percentage of non-fibrous contamination
JM 100 glass fiber	Timbrell Dust Generator (binder not noted)		100% ≤ 1 μm in diameter (EM); length 94.1% <5 μm (electron microscopy-EM) 48.4% 5-10 μm (light microscopy-LM) (96.6% [EM] and 41% [LM] respirable)	Wistar rats, 5 hr/d, 5 d/wk for 12 or 24 months. 332 WHO fibers/cm^3 (avg respirable dust concentrations at 12 months 6.34 mg/m^3; 5.39 mg/m^3 at 24 mo)		Lung: 12 and 24 mo: 9.18 and 15.32 mg/g dry tissue (62% clearance 16 mo post 12 mo exposure). No pulmonary or digestive tumors
Rock Wool	Resin free; brief milling	10 mg/m^3	42.6% of the fibers ≤ 1 μm in diameter and 5-20 μm in length	Sprague Dawley rats, 7 hr/d, 5 d/wk for 12 months. 227 WHO fibers/cm^3	UICC Canadian chrysotile (10 mg/m^3 equivalent to 3832 WHO fibers/cm^3) 82.3% of fibers with a diameter ≤1 μm between 5-20 μm in length. 25% tumor incidence; BAH noted in 5/48 animals. Retained dust 12 mo: 0.42 mg f/lung; 24 mo: 0.4 mg f/lung	12 mo: 3.11 mg f/lung; 24 mo 1.5 mg f/lung. 2/48; one animal had bronchoalveolar hyperplasia (BAH)	Wagner et al. 1984
Glass Wool	Resin free; brief milling		32.0% of fibers with a diameter of ≤1 μm and length between 5-20 μm	Sprague Dawley rats, 7 hr/d, 5 d/wk for 12 months. 323 WHO fibers/cm^3		12 mo: 0.94 mg f/lung; 24 mo 0.2 mg f/lung. 1/47 (benign adenoma); one incidence of BAH.
Glass Wool	Resin coating; brief milling		42.2% of fibers with a diameter of ≤1 μm and length between 5-20 μm	Sprague Dawley rats, 7 hr/d, 5 d/wk for 12 months. 240 WHO fibers/cm^3		12 mo: 1.88 mg f/lung; 24 mo 0.5 mg f/lung. 1/48 (adenocarcinoma); 3 BAH
JM 100 glass fiber	Not noted; brief milling		89.7% ≤ 1 μm in diameter and length between 5-20 μm; 71.2% were shorter than 10 µm	Sprague Dawley rats, 7 hr/d, 5 d/wk for 12 months. 1436 WHO fibers/cm^3		12 mo: 4.45 mg f/lung; 24 mo: 2.1 mg f/lung. 1/48 adenocarcinoma; three incidences of BAH

Table A5. Summary of nose-only inhalation toxicology studies of SVFs.

Fiber	Fiber prep	Exposure	Fiber dimensions	Exposure/aerosol concentrations	Controls	Outcomes	Reference
JM100 Glass Fibers (no binder)	Wetted with ethanol then placed in a plug-packing mold assembly (dried overnight); aerosolized through a Timbrell generator	3.0 or 0.3 mg/m^3	Mean diameter 0.45 µm, GMD 0.4 µm and geometric mean length [GML] 4.7 µm; 94% fibers ≤20 µm long	Osborne-Mendel rats and Syrian Golden hamsters 6 hr/d, 5 d/wk for 24 months. 3000 or 300 fibers/cm^3; mean 2.4 mg/m^3; particle:fiber ratio 4:1	UICC crocidolite (7 mg/m^3, 3000 fibers/cm^3) Rats 1/59, 1/61, and 3/57 (1 day, 30 day or 24 month exposure, respectively) 10, 36, or 53% fibrosis (1 day, 30 day and 24 month exposure, respectively); Hamsters no tumors at any time point, 2, 22, or 53% fibrosis (1 day, 30 day and 24 month exposure, respectively)	3 mg/m^3: Rats: 1.87 × 10^6 fibers/mg dry lung weight; Hamsters: 0.96 × 10^6 fibers/mg dry lung; 0.3 mg/m^3: Rats: 1.23 × 10^5 fibers/mg dry lung weight; Hamsters: 0.52 × 10^5 fibers/mg dry lung. 3 mg/m^3: Rats 0/57, fibrosis 7% Hamsters 0/69, fibrosis 6%; 0.3 mg/m^3: Rats 0/57, fibrosis 5% Hamsters 0/70, fibrosis 4%	Smith et al. 1987
Certainteed Glass Wool (silicone lubricant)		10 mg/m^3	Mean diameter 3.1 µm, GMD 1.2 µm and GML 24 µm; 99% of fibers were >5 µm, 77% >20 µm, and 68% fibers 10–80 µm long	Rats and hamsters 6 hr/d, 5 d/wk for 24 months. 100 fibers/cm^3; mean 4.4 mg/m^3; particle:fiber ratio 6:1		Rats: 2.85 × 10^4 fibers/mg dry lung weight; Hamsters: 1.15 × 10^4 fibers/mg dry lung. Rats 0/52, fibrosis 8%; Hamsters 0/60, fibrosis 3%
Manville building insulation (phenol-formaldehyde binder)		9 mg/m^3	Mean diameter 6.1 µm, GMD 3.0 µm, and GML 83 µm; approximately 53% fibers <2.5 µm diameter and 36% 10–80 µm long	Rats and hamsters 6 hr/d, 5 d/wk for 24 months. 25 fibers/cm^3; mean 7.0 mg/m^3; particle:fiber ratio 31:1		Rats: 5.72 × 10^2 fibers/mg dry lung weight; Hamsters: 5.05 × 10^2 fibers/mg dry *Retained dose low. Rats 0/58, fibrosis 5%; Hamsters 0/61 and 0/38, no fibrosis
Owens-Corning High Temperature Range Glass Wool (phenol-formaldehyde binder)		12 or 1.2 mg/m^3	Mean diameter 5.4 µm, GMD 1.1 µm, and GML 20 µm; 74% fibers <2.0 µm diameter and 67% 10-80 µm long	Rats and hamsters 6 hr/d, 5 d/wk for 24 months. 100 or 10 fibers/cm^3; mean 9.9 mg/m^3; particle:fiber ratio 38:1		12 mg/m^3: Rats: 1.0 × 10^3 fibers/mg dry lung weight; Hamsters: 2.35 × 10^3 fibers/mg dry lung; 1.2 mg/m^3: Rats: 1.11 × 10^3 fibers/mg dry lung weight; Hamsters: 0.73 × 10^2 fibers/mg dry lung *Retained dose low. 12.0 mg/m^3: Rats 0/57, fibrosis 7% Hamsters 1/66, no fibrosis; 1.2 mg/m^3: Rats 0/61, 8% fibrosis Hamsters 0/65, fibrosis 2%
RCF Carborundum Fibrefrax (no binder)		12 mg/m^3	Mean diameter 1.8 µm, GMD 0.9 µm, and GML 25 µm; 83% >10 µm long and 86% <2 µm in diameter	Rats and hamsters 6 hr/d, 5 d/wk for 24 months. 200 fibers/cm^3; 88 fibers/cm^3 >10 µm long and ≤1.0 µm diameter; mean 10.8 mg/m^3; particle:fiber ratio 33:1		Rats: 2.18 × 10^4 fibers/mg dry lung weight; Hamsters: 0.86 × 10^4 fibers/mg dry lung. Rats 0/55, fibrosis 22% Hamsters 1/70 (mesothelioma), 1% fibrosis
JV Spinner Slag Wool (no binder)		10 mg/m^3	Mean diameter 2.7 µm with a GMD of 0.9 µm and GML 22 µm; 93% of fibers had diameters <2.5 µm with 75% of fibers >10 µm long	Rats and hamsters 6 hr/d, 5 d/wk for 24 months. 200 fibers/cm^3; 76 fibers/cm^3 >10 μm in length and ≤1.0 μm in diameter; mean 7.8 mg/m^3; particle:fiber ratio 28:1		Rats: 3.08 × 10^3 fibers/mg dry lung weight; Hamsters: 3.07 × 10^3 fibers/mg dry lung. Rats 0/55, fibrosis 16% Hamsters 0/69, 1% fibrosis
JM 104/475 Glass Fibers (-/+ SO2)	Knife milled; Vibrating Bed Aerosol Generator	3.0 mg/m^3	Dimensions of 104/475 starting material not listed	Female Wistar rats; 5 hr/d, 4 d/wk for 6 wk and followed for 24 mo. 576 fibers/mL, 252 were >5 µm long, 90% fibers <0.80 µm and <12.4 µm length	Calidria chrysotile (6.0 mg/m^3; 241 f/ml total fibers, 131 f/ml >5 µm in length; 90% of aerosolized chrysotile was <1.6 µm diameter and <14.0 µm length) or UICC crocidolite (2.2 mg/m^3; 2011 total fibers/ml, 162 f/ml >5 µm in length); 74% animals exposed to crocidolite developed bronchoalveolar hyperplasia also one squamous metaplasia and one adenocarcinoma. No tumors in chrysotile group	104/475 (-SO2): 183, 310, and 187 x 10^6 fibers/lung; 104/475 (+SO2): 208, 340, and 233 x 10^6 fibers/lung; crocidolite: 403, 557, 229 x 10^6 fibers/lung; chrysotile: 398, 347, 223 x 10^6 fibers/lung all at 6, 12, and 24 mo, respectively. 104/475 (-SO2): Bronchoalveolar hyperplasia 11% (NS), one squamous metaplasia, one squamous cell carcinoma (107 animals); 104/475 (+SO2): Bronchoalveolar hyperplasia 16%, one adenoma (108 animals)	Muhle et al. 1987
MMVF 10 glass wool	Size-selected fine respirable fractions from commercial bulk products	3, 16, or 30 mg/m^3	Size selected stock: GMD 1.13 µm and GML 14.4 µm	Fischer F344 rats; 6 hr/d, 5 d/wk for 24 mo (3 or 6 animals sacrificed at 3, 6, 12, and 18 mo). 29.1 mg/m^3 (3 and 16 mg/m^3 aerosol not measured) Aerosolized: GMD 1.26 µm and GML 13.1 µm	10 mg/m^3 chrysotile (GMD 0.08 µm and GML of 1.2 µm) pulmonary fibrosis, mesothelioma, and significant increases in lung tumors in chrysotile exposed animals of 13/69 (18.9%)	30 mg/m^3: Highest levels at 24 mo: 4.16, 2.69, and 0.37 x 10^5 total fibers/mg dry tissue with 2.88, 1.85, and 0.24 x 10^5 WHO fibers for 30, 16, and 3 mg/m^3, respectively. No tumors observed in 3 mg/m^3 exposure group; one adenoma and no carcinomas in 16 mg/m^3 group; six adenomas and one carcinoma in 30 mg/m^3 exposure group.	Hesterberg et al. 1993
MMVF 11 glass wool	Size-selected fine respirable fractions from commercial bulk products	3, 16, or 30 mg/m^3	Size selected stock: GMD 0.76 µm and GML 13.0 µm	Fischer F344 rats; 6 hr/d, 5 d/wk for 24 months (3 or 6 animals sacrificed at 3, 6, 12, and 18 mo). 28.9 mg/m^3 (3 and 16 mg/m^3 aerosol not listed) Aerosolized: GMD of 0.69 µm and a GML of 13.7 µm		30 mg/m^3: Highest levels at 24 mo: 6.42, 3.46, and 0.62 x 10^5 fibers/mg dry tissue with 5.03, 2.35, and 0.48 x 10^5 WHO fibers for 30, 16, and 3 mg/m^3, respectively. Three adenomas and 1 carcinoma observed in 3 mg/m^3 exposure group; six adenomas and three carcinomas in 16 mg/m^3 group; three adenomas and no carcinomas in 30 mg/m^3 exposure group.
RCF1	Size-selected fine respirable fractions from commercial bulk products	30 mg/m^3	Size selected stock: GMD 0.86 µm and GMD 16.5 µm	Fischer F344 rats; 6 hr/d, 5 d/wk for 24 mo (3 or 6 animals sacrificed at 3, 6, 12, and 18 mo). 29.1 mg/m^3; Aerosolized: GMD 0.82 µm and GML 15.9 µm		30 mg/m^3: Highest levels at 18 mo: 4.67 x 10^5 total fibers/mg dry tissue with 3.57 x 10^5 WHO fibers; 24 mo: 3.70 x 10^5 total fibers/mg dry tissue with 2.75 x 10^5 WHO fibers. Pulmonary fibrosis, mesothelioma, tumor incidence 16/123 (13.0%)
MMVF21 Rock Wool			GMD about 0.95 µm and GML about 14 µm; WHO fibers/cm^3 of 34, 150 and 243; fibers >20 µm long 13, 74 and 114, respectively	6 hr/d, 5 d/wk for 18 months (Syrian Golden hamsters); or 24 months (Osborne-Mendel or Fisher 344 rats). 3.1 mg/m^3: 44 total fibers/cm^3 (34 WHO fibers/cm^3; GMD 0.94 x GML 13.0 µm); 16.1 mg/m^3: 185 total fibers/cm^3 (150 WHO fibers/cm^3; GMD 0.90 x GML 15.4 µm), or 30.4 mg/m^3: 264 total fibers/cm^3 (243 WHO fibers/cm^3; dimensions not given)	10 mg/m^3 crocidolite (GMD of 0.28 µm, determined by SEM, and a GML of 4.1 µm, determined by light microscopy; of 106 crocidolite-treated rats, ten had adenomas, six had pulmonary carcinomas and two had mesothelioma; crocidolite lung burdens were 759 x 10^3 WHO fibers (41.1 x 10^3 fibers >20 µm)	24 mo: 242 x 10^3 WHO fibers (39.5 x 10^3 fibers >20 µm) for the 30 mg/m^3 exposure, 217 x 10^3 WHO fibers (25.6 x 10^3 >20 µm) for the 16 mg/m^3 exposure, and 55.7 x 10^3 WHO fibers (9.0 x 10^3 >20 µm) for the 3 mg/m^3 exposure. Four lung adenomas (3.5%) and one lung carcinoma (0.8%) each were observed in the 3, 16 and 30 mg/m^3 rock wool exposure groups, respectively. Minimal focal fibrosis noted.	McConnell et al. 1994; IARC 2002
MMVF22 Slag Wool			GMD 0.85 µm and GML 13 µm, WHO fibers/cm^3 of 30, 131 and 213	6 hr/d, 5 d/wk for 18 months (Syrian Golden hamsters); or 24 months (Osborne-Mendel or Fisher 344 rats). 3.1 mg/m^3: 33 total fibers/cm^3 (30 WHO fibers/cm^3; GMD 0.84 x GML 12.3 µm); 16.1 mg/m^3: 158 total fibers/cm^3 (131 WHO fibers/cm^3; GMD 0.84 x GML 13.2 µm), or 29.9 mg/m^3: 245 total fibers/cm^3 (213 WHO fibers/cm^3; GMD 0.87 x GML 15.2 µm)		24 months was 177 × 10^3 (11.0 × 10^3 fibers >20 μm), for the 30 mg/m^3 exposure, 96.7 × 10^3 (4.5 × 10^3 fibers >20 μm) for the 16 mg/m^3 exposure and 44.4 × 10^3 WHO fibers (1.8 × 10^3 fibers >20 μm) for the 3 mg/m^3 exposure. One adenoma and one carcinoma were noted in the 3 mg/m^3 exposure; no tumors were observed in the group that received the 16 mg/m^3 exposure. In the group treated with 30 mg/m^3, two pulmonary adenomas and one lung carcinoma
Kaolin-Based RCF	Pre-sized fiber (1 µm diameter 22-26 µm long)	3, 9, 16, or 30 mg/m^3	215 WHO fibers/cm^3, mean diameter 0.9 µm and mean length 22.1 µm; also tested 16, 9, and 3 mg/m^3	Fischer F344 rats: 6 hr/d, 5 d/wk for 24 mo (terminal sacrifice at 29 mo); Hamsters: 6 hr/d, 5 d/wk for 18 mo (terminal sacrifice at 20 mo). 30 mg/m^3, 215 WHO fibers/cm^3, mean diameter 0.9 µm and mean length 22.1 µm; also tested 16, 9, and 3 mg/m^3	11 mg/m^3 chrysotile; 10,600 WHO fibers/cm^3, mean diameter 0.09 µm and mean length 2.17 µm. Incidence of bronchoalveolar neoplasms following chrysotile exposure was 18.8%; a single mesothelioma was noted. Lung burden 24 mo: 1.08 x 10^7	24 mo: Hamsters 2.39 x 10^5 f/mg dry lung Rats: 24 mo: 3.70 x 10^5, 2.70 x 10^5, 1.80 x 10^5, and 5.5 x 10^4 f/mg dry lung for 30, 16, 9, and 3 mg/m^3, respectively. Fibrosis Wagner Grade 4 for 30 and 16 mg/m^3 (rats and hamsters), Grade 3.2 for 3 mg/m^3; 14.6% tumor incidence in rats and no tumors in hamsters. Mesothelioma 1.6% (rats) and 42% (hamsters)	Mast et al. 1994
Zirconia Based RCF	Pre-sized fiber (1 µm diameter 22-26 µm long)	30 mg/m^3	224 WHO fibers/cm^3, mean diameter 1.0 µm and mean length 18.6 µm	Fischer F344 rats: 6 hr/d, 5 d/wk for 24 mo (terminal sacrifice at 29 mo); Syrian Golden hamsters: 6 hr/d, 5 d/wk for 18 mo (terminal sacrifice at 20 mo). 29 mg/m^3, 224 WHO fibers/cm^3, mean diameter 1.0 µm and mean length 18.6 µm		24 mo: 9.60 x 10^5 f/mg dry lung. Fibrosis Wagner Grade 4; 8.8% tumor incidence and 2.5% mesotheliomas
High-Purity RCF	pre-sized fiber (1 µm diameter 22-26 µm long)	30 mg/m^3	172 WHO fibers/cm^3, mean diameter 1.0 µm and mean length 24.2 µm	Fischer F344 rats: 6 hr/d, 5 d/wk for 24 mo (terminal sacrifice at 29 mo); Syrian Golden hamsters: 6 hr/d, 5 d/wk for 18 mo (terminal sacrifice at 20 mo). 29 mg/m^3, 172 WHO fibers/cm^3, mean diameter 1.0 µm and mean length 24.2 µm		24 mo: 2.70 x 10^5 f/mg dry lung. Fibrosis Wagner Grade 4.3; 16% tumor incidence and 1.7% mesothelioma incidence
After-Service RCF	Pre-sized fiber (1 µm diameter 22-26 µm long)	30 mg/m^3	166 WHO fibers/cm^3, mean diameter 1.3 µm and mean length 12.7 µm	Fischer F344 rats: 6 hr/d, 5 d/wk for 24 mo (terminal sacrifice at 29 mo); Syrian Golden hamsters: 6 hr/d, 5 d/wk for 18 mo (terminal sacrifice at 20 mo). 30 mg/m^3, 166 WHO fibers/cm^3, mean diameter 1.3 µm and mean length 12.7 µm		24 mo: 5.90 x 10^5 f/mg dry lung. Fibrosis Wagner Grade 4; 4% tumor incidence and 0.8% mesothelioma
Kaolin-Based RCF (RCF1)	Size-selected (approximately 1 µm diameter and approximately 20 µm length)	30 mg/m^3	Stock fiber dimensions: GMD 0.86 µm and GML 16.5 µm	Fischer F344 rat: 6 hr/d, 5 d/wk for 3, 6, 9, 12, 18, or 24 mo (terminal sacrifice at 20% survival 30 mo). 29.1 mg/m^3, 234 total fibers/cm^3 (187 WHO fibers/cm^3, GMD 0.82 µm and GML 15.9 µm; 43.2% of fibers >20 µm long	10 mg/m^3 chrysotile; (gravimetric 10.1 mg/m^3) 1.05 x 10^5 total fibers/cm^3 (1.06 x 10^5 WHO fibers/cm^3, GMD 0.85 µm and GML 15.9 µm; 43.2% of fibers >20 µm long. Highest level 9 mo: 367 x 10^5 fibers/mg of dry lung tissue (32 x 10^5 WHO fibers) 30 mo: 85 x 10^5 fibers/mg of dry lung tissue (4.25 x 10^5 WHO fibers). The incidence of bronchoalveolar neoplasms following chrysotile exposure was 18.8%; a single mesothelioma was noted. Air controls	Highest level 18 mo: 4.67 x 10^5 fibers/mg of dry lung tissue (3.57 x 10^5 WHO fibers) 30 mo: 1.7 x 10^5 fibers/mg of dry lung tissue (1.33 x 10^5 WHO fibers). 13% incidence of bronchoalveolar adenomas and carcinomas; two mesotheliomas; cellular and fibrotic histopathology grade 2-4.3	Mast et al. 1995a
Zirconia Based (RCF 2)	Size-selected (approximately 1 µm diameter and approximately 20 µm length)	30 mg/m^3	Stock fiber dimensions: GMD 0.91 µm and GML 14.6 µm	F344 Rats: 6 hr/d, 5 d/wk for 3, 6, 9, 12, 18, or 24 mo (terminal sacrifice at 20% survival 30 mo). 28.9 mg/m^3 268 total fibers/cm^3 (220 WHO fibers/cm^3), GMD 0.88 µm and GML 12.8 µm; 32.4% fibers >20 µm long		Highest level 18 mo: 9.82 x 10^5 fibers/mg dry lung tissue (7.97 x 10^5 WHO fibers) 30 mo: 1.68 x 10^5 fibers/mg dry lung tissue (1.35 x 10^5 WHO fibers). 7.4% incidence of bronchoalveolar adenomas and carcinomas; three mesotheliomas; cellular and fibrotic histopathology grade 2-4.2
High-Purity RCF (RCF 3)	Size-selected (approximately 1 µm diameter and approximately 20 µm length)	30 mg/m^3	Stock fiber dimensions: GMD 0.94 µm and GML 17.7 µm	F344 Rats: 6 hr/d, 5 d/wk for 3, 6, 9, 12, 18, or 24 mo (terminal sacrifice at 20% survival 30 mo). 29.2 mg/m^3 213 total fibers/cm^3 (182 WHO fibers/cm^3), GMD 0.85 µm and GML 17.4 µm; 47.9% of fibers >20 µm long		Highest level 18 mo: 3.23 x 10^5 fibers/mg dry lung tissue (2.60 x 10^5 WHO fibers) 30 mo: 1.92 x 10^5 fibers/mg dry lung tissue (1.45 x 10^5 WHO fibers). 15.7% incidence for bronchoalveolar adenomas and carcinomas; two mesotheliomas; cellular and fibrotic histopathology grade 2.3-4.7
After-Service RCF (RCF 4)	Size-selected (approximately 1 µm diameter and approximately 20 µm length)	30 mg/m^3	Stock fiber dimensions: GMD 1.1 µm and GML 7.0 µm	F344 Rats: 6 hours a day, 5 days per week for 3, 6, 9, 12, 18, or 24 mo (terminal sacrifice at 20% survival 30 mo). 30.1 mg/m^3 206 total fibers/cm^3 (153 WHO fibers/cm^3), GMD 1.2 µm and GML 9.0 µm; 16.4% fibers >20 µm long		Highest level 24 mo: 5.95 x 10^5 fibers/mg of dry lung tissue (3.48 x 10^5 WHO fibers) 30 mo: 4.56 x 10^5 fibers/mg of dry lung tissue (2.85 x 10^5 WHO fibers). 3.4% tumor incidence for bronchoalveolar adenomas and carcinomas; one mesothelioma; cellular and fibrotic histopathology grade 1-4.3
Kaolin-Based RCF	Size selected (approximately 1 µm in diameter and approximately 20 µm in length)	3, 9, or 16 mg/m^3 (compared to 30 mg/m^3 from Mast et al. 1995a	Stock fiber dimensions: GMD 0.86 µm and GML 16.5 µm	Fischer 344 rats: 6 hr/d, 5 d/wk for 24 mo (terminal sacrifice at 20% survival 30 mo). 26, 75, 120, or 187 WHO fibers/cm^3, GMD 0.82 µm and GML 1.5-16.8 µm	Compared to Mast et al. 1995a; air controls	30 mg/m^3: Highest level at 18 mo exposure/18 mo sacrifice: 46.70 x 10^4 total fibers (WHO fibers: 35.70 x 10^4); 24 mo: 37.0 x 10^4 (27.50 x 10^4 WHO fibers) 16 mg/m^3: Highest level 24 mo exposure/24 mo sacrifice: 27.8 x 10^4 total fibers (22.1 x 10^4 WHO fibers). Minimal to mild inflammation; Minimal interstitial fibrosis by 12 mo (9 and 16 mg/m^3) progressed to mild at 24 mo (16 mg/m^3). Tumor incidence (adenoma/carcinoma) 1.6%, 3.9%, 1.6% for 3, 9, or 16 mg/m^3. One mesothelioma at 9 mg/m^3	Mast et al. 1995b
MMVF 11 glass fiber	Counting and sizing per Bernstein et al. 1995	30 mg/m^3	Size selected stock: GMD of 0.69 µm and GML of 12 µm	Fischer F344 rats, 6 hr/d for 5 d, post-exposure 1 hr, 1 d, 5 d, 4 wk, 13 wk, and 26 wk. Gravimetric concentration 30 mg/m^3; 451 total fibers/cm^3 (377 WHO fibers/m^3) GMD 0.75 µm and GML 13 µm	Not evaluated	Highest level at 5 days: 6.3 x 10^6 total fibers/lung with 5.1 x 10^6 WHO fibers; 26 weeks: 0.35 x 10^6 total fibers/lung with 0.23 x 10^6 WHO fibers W-T1/2=32 days (fibers 5-20 µm long) W-T1/2=28 days (WHO fibers) Kdis @ pH 7.4 = 71 ng/cm^2/h; @ pH 4.5 = 0.7 ng/cm^2/h	Bernstein et al. 1996
A Glass Wool (soluble)			Size selected stock: GMD 0.56 µm and GMD 9.5 µm	Fischer F344 rats, 6 hr/d for 5 d, post-exposure 1 hr, 1 d, 5 d, 4 wk, 13 wk, and 26 wk. Gravimetric concentration 35 mg/m^3; 1127 total fibers/cm^3 (944 WHO fibers/m^3) GMD of 0.59 µm and a GML of 10 µm		Highest level at 5 days: 13.8 x 10^6 total fibers/lung with 9.3 x 10^6 WHO fibers; 26 weeks: 0.89 x 10^6 total fibers/lung with 0.52 x 10^6 WHO fibers W-T1/2=16 days (fibers 5-20 µm long) W-T1/2=15 days (WHO fibers) Kdis @ pH 7.4 = 129 ng/cm^2/h; @ pH 4.5 = 2.4 ng/cm^2/h
B-01/09			Size selected stock: GMD 0.52 µm and GMD 12 µm	Fischer F344 rats, 6 hr/d for 5 d, post-exposure 1 hr, 1 d, 5 d, 4 wk, 13 wk, and 26 wk. Gravimetric concentration 29 mg/m^3; 619 total fibers/cm^3 (541 WHO fibers/m^3) GMD of 0.48 µm and a GML of 11 µm		Highest level at 1 hour: 7.7 x 10^6 total fibers/lung with 5.1 x 10^6 WHO fibers; 13 weeks: 0.35 x 10^6 total fibers/lung with 0.18 x 10^6 WHO fibers W-T1/2=11 days (fibers 5-20 µm long) W-T1/2=11 days (WHO fibers) Kdis @ pH 7.4 = 320 ng/cm^2/h; @ pH 4.5 = 11.8 ng/cm^2/h
C Glass Wool (soluble)			Size selected stock: GMD 0.56 µm and GMD 13 µm	Fischer F344 rats, 6 hr/d for 5 d, post-exposure 1 hr, 1 d, 5 d, 4 wk, 13 wk, and 26 wk. Gravimetric concentration 30 mg/m^3; 709 total fibers/cm^3 (589 WHO fibers/m^3) GMD of 0.43 µm and a GML of 11 µm		Highest level at 1 hour: 12.1 x 10^6 total fibers/lung with 7.9 x 10^6 WHO fibers; 26 weeks: 0.15 x 10^6 total fibers/lung with 0.07 x 10^6 WHO fibers W-T1/2=15 days (fibers 5-20 µm long) W-T1/2=14 days (WHO fibers) Kdis @ pH 7.4 = 309 ng/cm^2/h; @ pH 4.5 = 6.2 ng/cm^2/h
J (X-607, soluble)			Size selected stock: GMD 0.51 µm and GMD 11 µm	Fischer F344 rats, 6 hr/d for 5 d, post-exposure 1 hr, 1 d, 5 d, 4 wk, 13 wk, and 26 wk. Gravimetric concentration 31 mg/m^3; 804 total fibers/cm^3 (643 WHO fibers/m^3) GMD of 0.54 µm and a GML of 10 µm		Highest level at 1 hour: 7.4 x 10^6 total fibers/lung with 4.8 x 10^6 WHO fibers; 26 weeks: 0.48 x 10^6 total fibers/lung with 0.25 x 10^6 WHO fibers W-T1/2=24 days (fibers 5-20 µm long) W-T1/2=23 days (WHO fibers) Kdis @ pH 7.4 = 104 ng/cm^2/h; @ pH 4.5 = 4.3 ng/cm^2/h
F Stone Wool			Size selected stock: GMD 0.5 µm and GMD 9.4 µm	Fischer F344 rats, 6 hr/d for 5 d, post-exposure 1 hr, 1 d, 5 d, 4 wk, 13 wk, and 26 wk. Gravimetric concentration 31 mg/m^3; 899 total fibers/cm^3 (708 WHO fibers/m^3) GMD of 0.66 µm and a GML of 9.9 µm		Highest level at 1 hour: 15.6 x 10^6 total fibers/lung with 9.0 x 10^6 WHO fibers; 26 weeks: 0.62 x 10^6 total fibers/lung with 0.36 x 10^6 WHO fibers W-T1/2=28 days (fibers 5-20 µm long) W-T1/2=28 days (WHO fibers) Kdis @ pH 7.4 = 96 ng/cm^2/h; @ pH 4.5 = 5.9 ng/cm^2/h
G Stone Wool			Size selected stock: GMD 0.67 µm and GMD 11 µm	Fischer F344 rats, 6 hr/d for 5 d, post-exposure 1 hr, 1 d, 5 d, 4 wk, 13 wk, and 26 wk. Gravimetric concentration 30 mg/m^3; 981 total fibers/cm^3 (832 WHO fibers/m^3) GMD of 0.46 µm and a GML of 11 µm		Highest level at 1 hour: 10.0 x 10^6 total fibers/lung with 6.4 x 10^6 WHO fibers; 26 weeks: 0.33 x 10^6 total fibers/lung with 0.17 x 10^6 WHO fibers W-T1/2=23 days (fibers 5-20 µm long) W-T1/2=22 days (WHO fibers) Kdis @ pH 7.4 = 129 ng/cm^2/h; A pH 4.5 = 4.1 ng/cm^2/h
H Stone Wool			Size selected stock: GMD 0.66 µm and GMD 13 µm	Fischer F344 rats, 6 hr/d for 5 d, post-exposure 1 hr, 1 d, 5 d, 4 wk, 13 wk, and 26 wk. Gravimetric concentration 30 mg/m^3; 351 total fibers/cm^3 (299 WHO fibers/m^3) GMD of 0.68 µm and a GML of 13 µm		Highest level at 1 hour: 9.5 x 10^6 total fibers/lung with 6.7 x 10^6 WHO fibers; 26 weeks: 0.47 x 10^6 total fibers/lung with 0.33 x 10^6 WHO fibers W-T1/2=27 days (fibers 5-20 µm long) W-T1/2=26 days (WHO fibers) Kdis @ pH 7.4 = 169 ng/cm^2/h; @ pH 4.5 = 5.5 ng/cm^2/h
L Commercial Stone Wool			Size selected stock: GMD 0.63 µm and GMD 16.9 µm	Fischer F344 rats, 6 hr/d for 5 d, post-exposure 1 hr, 1 d, 5 d, 4 wk, 13 wk, and 26 wk. Gravimetric concentration 31 mg/m^3; 478 total fibers/cm^3 (420 WHO fibers/m^3) GMD of 0.51 µm and a GML of 15 µm		Highest level at 1 hour: 5.7 x 10^6 total fibers/lung with 4.0 x 10^6 WHO fibers; 26 weeks: 0.30 x 10^6 total fibers/lung with 0.23 x 10^6 WHO fibers W-T1/2=57 days (fibers 5-20 µm long) W-T1/2=54 days (WHO fibers) Kdis @ pH 7.4 = 23 ng/cm^2/h; @ pH 4.5 = 342 ng/cm^2/h
MMVF10 Glass Wool	Size-selected	30 mg/m^3	Details for each fiber type not given; approximate arithmetic mean 1 x 20 µm to simulate workplace exposure	Fischer F344 rats, 6 hr/d, 5 d/wk for 24 mo (3 or 6 animals sacrificed at 3, 6, 12, and 18 mo). 32 mg/m^3; Aerosolized: GMD of 1.1 µm and a GML of 11 µm	10 mg/m^3 Crocidolite (NIEHS) GMD 0.2 µm x GML 3 µm; Aerosolized: 11 mg/m^3; GMD of 0.3 µm and a GML of 4.2 µm. W-T1/2=986 days (fibers >20 µm long) W-T1/2=234 days (WHO fibers); 61% of WHO fibers retained (day 1 vs day 365)	1 d: 0.14 x 10^6 total fibers/lung >20 µm long and 2.8 x 10^6 WHO fibers; 365 d: 2.0 x 10^3 total fibers/lung >20 µm long with 3.0 x 10^5 WHO fibers W-T1/2=44 d (fibers >20 µm long) W-T1/2=89 d (WHO fibers); 11% of WHO fibers retained (d 1 vs d 365)	Hesterberg et al. 1996
CertainTeed B MMVF11 Glass Wool				Fischer F344 rats, 6 hr/d, 5 d/wk for 24 mo (3 or 6 animals sacrificed at 3, 6, 12, and 18 mo). 29 mg/m^3; Aerosolized: GMD of 0.7 µm and a GML of 12 µm		1 d: 0.97 x 10^6 total fibers/lung >20 µm long and 5.6 x 10^6 WHO fibers; 365 d: 2.0 x 10^3 total fibers/lung >20 µm long with 2.0 x 10^5 WHO fibers W-T1/2=6 d (fibers >20 µm long) W-T1/2=35 d (WHO fibers); 4% of WHO fibers retained (d 1 vs d 365)
Rockwool Intl MMVF21 Rock Wool				Fischer F344 rats, 6 hr/d, 5 d/wk for 24 mo (3 or 6 animals sacrificed at 3, 6, 12, and 18 mo). 31 mg/m^3; Aerosolized: GMD of 0.9 µm and a GML of 16 µm		1 d: 0.55 x 10^6 total fibers/lung >20 µm long and 1.8 x 10^6 WHO fibers; 365 d: 2.0 x 10^4 total fibers/lung >20 µm long with 1.0 x 10^5 WHO fibers W-T1/2=53 d (fibers >20 µm long) W-T1/2=111 d (WHO fibers); 8% of WHO fibers retained (d 1 vs d 365)
USG Interiors MMVF22 Slag Wool (oil treated)				Fischer F344 rats, 6 hr/d, 5 d/wk for 24 mo (3 or 6 animals sacrificed at 3, 6, 12, and 18 mo). 30 mg/m^3; Aerosolized: GMD of 0.9 µm and a GML of 15 µm		1 d: 0.40 x 10^6 total fibers/lung >20 µm long and 3.4 x 10^6 WHO fibers; 365 d: 1.0 x 10^3 total fibers/lung >20 µm long with 1.0 x 10^5 WHO fibers W-T1/2=5 d (fibers >20 µm long) W-T1/2=75 d (WHO fibers); no WHO fibers retained (d 1 vs d 365)
RCF-1	Not listed	Average of 45.6 mg/m^3 650 fibers/cc; 300 WHO fibers/cc	Fibers with an aspect ratio >3:1 GMD 1.8 µm and GML 2.5 µm (65% of aerosol) and particles with aspect ratio <3:1 (35% of aerosol), GMD 1.62 µm and GML 1.58 µm	Fischer F344 rats and Syrian Golden hamsters, 4 hr/d, 5 d/wk for 12 wk. GMD 0.63 µm and GML 5.3 µm; 35% non-fiber particle	No positive control	Pleural fiber burden - Hamster: 4 wks 17.5 x 10^3, 12 wks: 14.8 x 10^3, 24 mo: 15.6 x 10^3 total fibers; Rat: 4 wks 42.1 x 10^3, 12 wks: 41.4 x 10^3, 24 mo: 40.3 x 10^3 total fibers. Rats and hamsters - pleural inflammation. Mesothelial cell proliferation more pronounced in hamsters than in rats. Mesothelial cell labeling index was highest in parietal pleural mesothelial cells lining the surface of the diaphragm (rats and hamsters). Hamsters but not rats had significantly elevated collagen in the visceral pleura at 12 wk.	Everitt et al. 1997
RCF1a	Size-selected for rat respirability	Target 150 fibers/cc > 20 µm long	Stock fiber dimensions not listed	Fischer rats, 62 mg/m^3 351 WHO fibers/cc and 145 fibers >20 µm, GMD 0.79 µm x GML 13.6 µm	Amosite (17 mg/m^3, GMD 0.48 µm, GML 7.7 µm); WT1/2 >400 days	Highest level d 2: 20 x 10^5 fibers/lung >20 µm length, d 365: 0.6 x 10^5 fibers/lung >20 µm length (4% of d 1); Recovered fibers: GMD 0.54 µm x GML 7.0 µm W-T1/2=55 d 90% Clearance = 227 d (fibers >20 µm long) Kdis @ pH 7.4 = 3 ng/cm^2/h	Hesterberg et al. 1998b
MMVF21 Rock Wool				Fischer rats, 58 mg/m^3 466 WHO fibers/cc and 138 fibers >20 µm, GMD 0.86 µm x GML 11.9 µm		Highest level d 7: 12 x 10^5 fibers/lung >20 µm length, d 365: 1 x 10^5 fibers/lung >20 µm length (5% of d 1); GMD 0.61 µm x GML 7.1 µm W-T1/2=67 d 90% Clearance = 264 d (fibers > 20 µm long) Kdis @ pH 7.4 = 20 ng/cm^2/h
MMVF22 Slag Wool						Kdis @ pH 7.4 = 400 ng/cm^2/h
MMVF32 E Glass Fiber				Fischer rats, 51 mg/m^3 316 WHO fibers/cc and 146 fibers >20 µm, GMD 0.81 µm x GML 16.1 µm		Highest level d 2: 14 x 10^5 fibers/lung >20 µm length, d 365: 1 x 10^5 fibers/lung >20 µm length (10% of d 1); GMD 0.47 µm x GML 8.9 µm W-T1/2=79 d 90% Clearance = 371 d (fibers > 20 µm long) Kdis @ pH 7.4 = 9 ng/cm^2/h
MMVF33 475 Glass Fiber				Fischer rats, 51 mg/m^3 371 WHO fibers/cc and 163 fibers >20 µm, 51 mg/m^3 GMD 0.74 µm x GML 16.2 µm		Highest level d 1: 13 x 10^5 fibers/lung >20 µm length, d 365: 0.8 x 10^5 fibers/lung >20 µm length (6% of d 1); GMD 0.39 µm x GML 8.2 µm W-T1/2=49 d 90% Clearance = 240 d (fibers >20 µm long) Kdis @ pH 7.4 = 12 ng/cm^2/h
MMVF34 (HT Stone Wool)				Fischer rats, 60 mg/m^3 367 WHO fibers/cc and 160 fibers >20 µm, GMD 0.73 µm x GML 13.2 µm		Highest level d 1: 15 x 10^5 fibers/lung >20 µm length, d 365: <0.01 fibers/lung (0.04% of d 1); GMD 0.48 µm x GML 7.3 µm W-T1/2=6 d 90% Clearance = 19 d (fibers > 20 µm long) Kdis @ pH 7.4 = 59 ng/cm^2/h
MMVF21 Stone Wool	Size-selected for rat respirability	60 mg/m^3; Target 150 fibers/cm^3 > 20 µm long	Not listed	Male Fischer F344 rats, 6 hr/d for 5 d, post exposure 12 mo. 58 mg/m^3, 467 WHO fibers/cm^3, 147 fibers/cm^3 >20 µm long	No positive control	Highest level d 2: 8.0 x 10^6 WHO fibers/lung, 1.1 x 10^6 fibers >20 µm; d 365: 0.5 x 10^6 WHO fibers/lung (6% of day 1), 0.1 x 10^6 fibers >20 µm T 1/2=65 d for WHO fibers; 92 d for fibers > 20 µm Kdis @ pH 7.5 = 23 (16-30) ng/cm^2/h; @pH 4.5 = 59 (41-77) ng/cm^2/h (based on Si)	Kamstrup et al. 1998
MMVF34 HT Stone Wool				Male Fischer F344 rats, 6 hr/d for 5 d, post exposure 12 mo. 60 mg/m^3, 370 WHO fibers/cm^3, 161 fibers/cm^3 > 20 µm long		Highest level d 2: 10.6 x 10^5 WHO fibers/lung, 1.3 x 10^6 fibers >20 µm; d 365: 0 WHO fibers/lung or fibers >20 µm T 1/2=22 d for WHO fibers; 5 d for fibers >20 µm Kdis @ pH 7.5 = 59 (41-77) ng/cm^2/h; @ pH 4.5 = 620 (434-806) ng/cm^2/h (based on Si)
X-607	Size-selected fine respirable fractions from commercial bulk products	30 mg/m^3 (target conc 180 WHO fibers/cc)	Mean dimensions across all fiber types 1 x 20 µm	Fischer 344 rats, 6 hr/d, 5 d/wk for 2 years. 30 mg/m^3 average of 174 WHO fibers/m^3; 47 fibers >20 µm long; GMD 0.9 μm x GML 11 μm	10 mg/m^3 Chrysotile 10,600 fibers/cc Mild macrophage aggregation, alveolar bronchiolization, microgranulation and bronchoalvelar collagen deposition. Tumor induction 17.4%, 1 pleural mesothelioma.	2 yrs no recovery: 187 x 10^3 WHO fibers with 4 x 10^3 >20 µm; Recovered fiber dimensions 0.5 diameter x 6 length µm. Highest level: 78 wks/26 wks recovery 13.3 x 10^6 WHO fibers (16% of exposure retained) with no fibers >20 µm. Mild macrophage aggregation and cellularity; some microgranulation noted by 78 weeks. Tumor induction 1.6% and no pleural mesotheliomas	Hesterberg et al. 1998a
RCF1				Fischer 344 rats, 6 hr/d, 5 d/wk for 2 yr. 29 mg/m^3 average of 187 WHO fibers/m^3; 101 WHO fibers >20 µm long		2 yrs no recovery: 275 x 10^3 WHO fibers with 48 x 10^3 >20 µm; Recovered fiber dimensions 0.5 diameter x 8 length µm. Highest level: 78 wks/26 wks recovery 87.7 x 10^6 WHO fibers (51% of exposure retained) with 6.89 x 10^6 fibers >20 µm (33% of exposure counts retained). Mild macrophage aggregation, cellularity microgranulation, bronchoalveloar collagen deposition, minimal pleura collagen deposition. Moderate pulmonary change Wagner Score (4). Tumor induction 12.4%, 1.7% mesothelioma
MMVF21 Stone Wool	Size-selected for rat respirability	16 or 30 mg/m^3	Not listed	Male Fischer 344 rats, 6 hr/d for 5 d/wk for 2 yr, interim sacrifices at 3, 6, 12, 18, 24 mo. 16 mg/m^3 150 WHO fibers/cm^3 with 74 fibers/cm^3 >20 µm long ; 30 mg/m^3: 243 WHO fibers/cm^3 with 114 fibers/cm^3 >20 µm long	No positive control	16 mg/m^3 3 mo: 38.0 x 10^3 WHO fibers/lung, 8x 10^3 fibers >20 µm 6 mo: 85 x 10^3 WHO fibers/lung and 16 x 10^3 fibers >20 µm 12 mo: 210 x 10^3 WHO fibers/lung and 37 x 10^3 fibers >20 µm 18 mo: 233 x 10^3 WHO fibers/lung and 58 x 10^3 fibers >20 µm 30.4 mg/m^3 3 mo: 243x 10^3 WHO fibers/lung, 114x 10^3 fibers >20 µm 6 mo: 143 x 10^3 WHO fibers/lung and 23 x 10^3 fibers >20 µm 12 mo: 319 x 10^3 WHO fibers/lung and 55 x 10^3 fibers >20 µm 18 mo: 283 x 10^3 WHO fibers/lung and 62 x 10^3 fibers longer than 20 µm. 16 mg/m^3: Wagner scores ranged from 2.2 (minimal cellular change) at 3 mo to 4 at 18 mo (minimal fibrosis), 30.4 mg/m^3: Wagner scores ranged from 3.2 (mild cellular change) at 3 mo to 4 (minimal fibrosis) at 18 mo	Kamstrup et al. 1998
MMVF34 HT Stone Wool	Size-selected for rat respirability	30 mg/m^3 (3, 12, or 18 mo exposure)	Not listed	Male Fischer 344 rat, 6 hr/d, 5 d/wk for 2 yr, interim sacrifices at 3, 6, 12, 18, 24 mo. 31 mg/m^3 3 mo: 282 WHO fibers/cm^3 with 84 fibers/cm^3 >20 µm long; 12 mo: 264 WHO fibers/cm^3 with 82 fibers/cm^3 >20 µm long; 18 mo: 288 WHO fibers/cm^3 with 86 fibers/cm^3 >20 µm long		30.5 mg/m^3 3 mo: 288 x 10^3 WHO fibers/lung, 86 x 10^3 fibers >20 µm 6 mo: 147 x 10^3 WHO fibers/lung and 11 x 10^3 fibers >20 µm 12 mo: 152 x 10^3 WHO fibers/lung and 10 x 10^3 fibers >20 µm 18 mo: 222 x 10^3 WHO fibers/lung and 11 x 10^3 fibers >20 µm. Interstitial fibrosis Wagner scores ranged from 1.6 (normal approaching minimal) at 3 mo to 2.8 (approaching mild)
MMVF10a Glass Fiber	Size-selected to be rat respirable	30 mg/m^3	0.84 μm × 12.4 μm	Syrian Golden hamsters, 6 hr/d, 5 d/wk for 78 wk (18 mo); Select animals evaluated at 13, 26, 52, and 78 wk exposure. 29.6 mg/m^3 (mean diameter 0.95 x mean length 19.4 µm) 339 WHO fibers/cm^3, including 134 fibers >20 μm/cm^3	Amosite asbestos (36, 165, or 263 WHO fibers/cm^3 with a GMD of 0.48 µm and a GML of 7.7 µm); severe pulmonary fibrosis and multiple mesotheliomas; 6 hr lung burden: 20.8 × 10^5 WHO fibres/lung (2 fibres >20 μm) at 78 wk lung burden 144 × 10^6. No pulmonary neoplasms, mesotheliomas 3.6%, 25.9%, and 19.5%	6 hr deposition: 8.4 × 10^5 WHO fibers/lung (1.6 x 10^5 fibers >20 μm long); 78 wks: 76.7 × 10^6 WHO fibers (4.6 × 10^6 fibers >20 μm long) 78 wks+ 6 wks of recovery: 27.8 × 10^6 WHO fibers (0.23 × 10^6 fibers >20 μm long). Lung inflammation with recovery by 6 wks; no fibrosis or neoplasms	McConnell et al. 1999
JM475 (MMVF33) Glass Fiber	Size-selected to be rat respirable	37 mg/m^3	0.7 μm × 11.8 μm	Syrian Golden hamsters, 6 hr/d, 5 d/wk for 78 wk (18 mo); Select animals evaluated at 13, 26, 52, and 78 wk exposure. 37 mg/m^3 (mean diameter 0.9 x mean length 16.9 µm) 310 WHO fibers/cm^3, including 109 fibers >20 μm/cm^3		6 hr deposition: 11.5 × 10^5 WHO fibers, (2.2 × 10^5 fibers >20 μm) 78 wks: 234 × 10^6 WHO fibers (30 × 10^6 fibers >20 μm long) 78 wks+ 6 wks of recovery: 141 × 10^6 WHO fibers (11.3 × 10^6 fibers >20 μm long). Inflammation and mild fibrosis by 26 wk, more severe by 52 wk. Pleural hyperplasia, 1 mesothelioma
MMVF34 HT Stone Wool Fiber	Size-selected to be rat respirable	30 mg/m^3	Stock fiber dimensions: GMD 0.98 µm and GML 11.1 µm)	Male Fischer F344 rats 6 hr/d, 5 d/wk for 104 wk (interim sacrifices at 13, 26, 52, and 104 wk). 30.1 mg/m^3: mean concentration 400 fibers/cm^3 (291 WHO fibers/cm^3) with 85 fibers/cm^3 that were >20 µm in length; GMD 0.87 µm and GML 10.8 µm	No positive control group	Highest level at 12 mo 192.3 x 10^6 total fibers (WHO fibers highest 12 months: 80.3 x 10^6); 24 mo: 108.5 x 10^6 total fibers (60.2 WHO fibers). Interstitial collagen/fibrosis 0.5% at 24 mo; adenomas 4.7% (NS from control), no carcinomas	Kamstrup et al. 2001
MMVF21 Stone Wool	Size-selected to be rat respirable	3, 16, or 30 mg/m^3	Stock fiber dimensions: GMD 1.09 µm and GML 16.1 µm	Male Fischer F344 rats 6 hr/d, 5 d/wk for 104 wk (interim sacrifices at 13, 26, 52, and 104 wk). 30.4 mg/m^3: 264 total fibers/cm^3 (243 WHO) with GMD 0.98 µm and GML 16.5 µm, 43% of fibers were >20 µm in length; 16.2 mg/m^3: 185 total fibers/cm^3 (150 WHO), GMD 0.90 µm and GML 15.4 µm, 40% fibers > 20 µm length	No positive control group	30 mg/m^3: Highest level at 24 mo 110.1 x 10^6 total fibers (WHO fibers highest 12 mo: 94.1 x 10^6); 24 mo: 87.6 x 10^6 WHO fibers 16 mg/m^3: Highest level at 24 mo: 95.2 x 10^6 total fibers (24 mo 67.8 x 10^6 WHO fibers) ** 3 mg data not listed. 30 mg/m^3: interstitial collagen/fibrosis 5.04% at 18 mo (decreased to 3.84% at 24 mo); 3.5% adenomas, 0.9% carcinoma (NS from control) 16 mg/m^3: interstitial collagen/fibrosis highest level 1.68% at 24 mo; 3.5% adenomas, 0.9% carcinoma (NS from control)
RCF1	Standard for RCC studies	50 mg/m^3	Target concentration: 130 fibers/ml > 20 µm	Female Wistar rats; 6 hr/d, 5 d/wk for 3 wk. 51.2 mg/m^3; 10% fibers were >20 µm and 90% were <20 µm; GMD 0.79 µm x GML 6.8 µm	No positive control group	3d post inhalation: 3.3 x 10^6 /lung >20 µm and 46.5 x 10^6 /lung <20 µm; 102.4 x 10^6 non-fibrous particles. Biochemical and cytological analyses in BALF at days 3, 17, 31, 94, and 365 d post exposure showed inflammation in RCF1 animals was more persistent compared to RCF1a animals.	Bellmann et al. 2001; Brown et al. 2000 from IARC 2002
RCF1a	less "aggressive" preparation resulting in longer fibers longer and lower levels of nonfibrous particles	25 mg/m^3	Target concentration: 125 fibers ml > 20 µm	Female Wistar rats; 6 hr/d, 5 d/wk for 3 wk. 25.8 mg/m^3; 19% fibers were >20 µm and 81% were <20 µm; GMD 0.49 µm x GML 7.8 µm	No positive control group	3d post inhalation: 5.0 x 10^6/lung >20 µm and 32.7 x 10^6/lung <20 µm; 6.9 x 10^6 non-fibrous particles. Half time based on alveolar tracer clearance= 80 days (range 71-91 days)
JM901	Size-selected rat respirable (high concentration of long, thin fibers w/ diameter <1 μm and length >20 μm)	13 mgm^3	Stock fiber dimensions not given	Fischer F344 rats, 6 hr/d for 5 d, 13 mg/m^3, 403 WHO fibers/cm^3 (104 fibers >20 µm/cm^3), GMD 0.63 µm and GML 10.3 µm	Amosite 5 mg/m^3 Health outcomes: Day 1: Significantly increased LDH, total protein, eosinophils, leukocytes, and neutrophils; decreased macrophages in BALF. Significantly increased eosinophils in pleural lavage. Day 14: Significant increase in neutrophils in BALF and total protein, macrophages, eosinophils, and mast cells in pleural lavage. Day 29-30: Significantly increased leukocytes and neutrophils in BALF and total protein, macrophages, and eosinophils in pleural lavage.	90d: 2.9 x 10^6 WHO fibers/lung, peak burden 1d: 8.6 x 10^6 WHO fibers/lung (1.6 x 10^6 WHO fibers/lung at 181 d). W-T1/2 = 9.8 d (fibers >20 µm long) 90% Clearance = 69 d Kdis @ pH 7.4= NT. Day 1: Significantly increased LDH, total protein and neutrophils and significantly decreased macrophages in BALF; significantly increased eosinophils in pleural lavage. Day 14: Significant increase in neutrophils in BALF and macrophages and eosinophils in pleural lavage. Day 29-30: Significant increase in pleural macrophages.	Hesterberg et al. 2002
JM901F		12 mg/m^3		Fischer F344 rats, 6 hr/d for 5 d, 14 mg/m^3, 401 WHO fibers/cm^3 (173 fibers >20 µm/cm^3), GMD 0.71 µm and GML 12.7 µm		91d: 1.8 x 10^6 WHO fibers/lung, peak burden 1 d: 9.5 x 10^6 WHO fibers/lung (0.6 x 10^6 WHO fibers/lung at 182 d). W-T1/2 = 8.1 d (fibers >20 µm long) 90% Clearance = 38 d Kdis @ pH 7.4 = 500 ng/cm^2/h. Day 1: Significantly increased LDH, total protein and neutrophils in BALF and total protein in pleural lavage. Day 14: Significantly increased pleural total protein. Day 29-30: NS
JM902		32 mg/m^3		Fischer F344 rats, 6 hr/d for 5 d, 32 mg/m^3, 443 WHO fibers/cm^3 (119 fibers >20 µm/cm^3), GMD 0.51 µm and GML 10.9 µm		90d: 2.1 x 10^6 WHO fibers/lung, peak burden 1 d: 11.7 x 10^6 WHO fibers/lung. W-T1/2 = 6.8 d (fibers >20 µm long) 90% Clearance = 33 d Kdis @ pH 7.4 = 150 ng/cm^2/h. Day 1: Significantly increased LDH, total protein and neutrophils in BALF. Day 14: Significantly increased pleural macrophages and mast cells. Day 29-30: Significant increase in eosinophils in pleural lavage.
JM475 (MMVF33)		21 mg/m^3		Fischer F344 rats, 6 hr/d for 5 d, 21 mg/m^3, 405 WHO fibers/cm^3 (166 fibers >20 µm/cm^3), GMD 0.51 µm and GML 10.9 µm		90d: 1.6x 10^6 WHO fibers/lung, peak burden 1 d: 7.1 x 10^6 WHO fibers/lung (0.5 x 10^6 WHO fibers/lung at 365 d). W-T1/2 = 49 d (fibers >20 µm long) 90% Clearance = 240 d Kdis @ pH 7.4 = 12 ng/cm^2/h. Day 1: Significantly increased LDH, total protein, eosinophils, leukocytes, and neutrophils in BALF and total protein and eosinophils in pleural lavage. Significant decrease in BALF macrophages. Day 14: Significant increase in total protein, macrophages, mast cells and eosinophils in pleural lavage. Day 29-30: Significantly increased LDH, beta-glucuronidase, total protein, leukocytes in BALF and total protein, macrophages, and eosinophils in pleural lavage.
E-Glass Fiber	Counting and sizing per WHO guidance (1985)	15, 50, or 150 f/ml (fiber length >20 µm)	Size selected stock: GMD 0.34 µm and GMD 5.22 µm	Male Wistar rats, 6 hr/d, 5 d/wk for 3 mo. 17.2 mg/m^3	No positive control; Included air control	1 wk exposure: 17 × 10^6 fibers > 20 μm per lung. After 3 mo recovery, decreased to 38.4% of original burden. W-T1/2 =57-63 d (fibers >20 µm long) Increased lung weight, biochemical parameters and polymorphonuclear leukocytes (PMN) in BAL, in cell proliferation (BrdU-response) and interstitial fibrosis. The values observed in the proliferation assay on the carcinogenic E-glass microfiber indicate that this assay has an important predictive value with regards to potential carcinogenicity.	Bellmann et al. 2003
MMVF21			Size selected stock: GMD 0.92 µm and GMD 10.85 µm	Male Wistar rats, 6 hr/d, 5 d/wk for 3 mo. 37 mg/m^3		1 wk: 5.7 × 10^6 fibers >20 μm per lung. After 3 mo recovery, decreased to 63.9% of original burden. W-T1/2=28-140 d (fibers >20 µm long)
High Temp CMS fiber (calcium-magnesium-silicate)		150 f/ml (fiber length >20 µm)	Size selected stock: GMD 0.94 µm and GMD 10.1 µm	Male Wistar rats, 6 hr/d, 5 d/wk for 3 mo. 49.5 mg/m^3		1 wk: 0.88 × 10^6 fibers >20 μm per lung. After 3 mo recovery, decreased to 3% of original burden. W-T1/2 fibers >20 µm long = 8 d
MMVF10a Glass Fiber	As described in Gelzleicher et al. 1996a	Target mass 45 mg/m^3	Not listed	Fischer F344 rats, Syrian Golden hamsters: 4 hr/d for 5 d/wk for either 4 or 12 wk. 45 mg/m^3 (610 WHO fibers/cc)	No positive control	Hamster: 160 fibers/cm^2; Rats: 60 fibers/cm^2. Pleural inflammatory responses minimal. Rats: pleural inflammation w/ increased #s of macrophages, increases in mesothelial cell replication. Hamsters: increased #s of macrophages and lymphocytes, and mesothelial-cell replication elevated on parietal pleura; some responses persisting through 12 wk of postexposure recovery.	Bermudez et al. 2003
E-Glass	Not described	15, 50, or 150 f/ml	Stock fiber dimensions (fibers >20 µm): GMD 0.52 µm and GML 34.31 µm	Male Wistar rats; 6 hr/d, 5 d/wk for 3 mo. Gravimetric exposure: 150 f/ml, 17.2 mg/m^3; aerosol fibers >20 µm in length: 15 f/ml: GMD 0.56 µm x GML 31.4 µm; 50 f/ml: GMD 0.57 µm x GML 30.6 µm; 150 f/ml: GMD 0.57 µm x GML 31.1 µm	No positive control	For fibers > 20 µm in length: 17 x 10^6; after 3 mo recovery 38.4% remaining. Increase in lung weights; BAL LDH, b-glucuronidase, and protein; interstitial fibrosis-EPA score 2 (50/150 f/ml)	Bellmann et al. 2003
MMVF21	Not described	15, 50, or 150 f/ml	Stock fiber dimensions (fibers >20 µm): GMD 1.13 µm and GML 35.25 µm	Male Wistar rats; 6 hr/d, 5 d/wk for 3 mo. Gravimetric exposure: 150 f/ml, 38 mg/m^3; aerosol fibers >20 µm in length: 15 f/ml: GMD 0.88 µm x GML 33.0 µm; 50 f/ml: GMD 0.91 µm x GML 33.7 µm; 150 f/ml: GMD 0.93 µm x GML 33.1 µm	No positive control	For fibers >20 µm in length: 5.7 x 10^6; after 3 mo recovery 63.9% remaining. Increase in lung weights; BAL LDH, b-glucuronidase, and protein; interstitial fibrosis- EPS score 2 (50/150 f/ml),
CMS (Calcium-magnesium- silicate)	Not described	150 f/ml	Stock fiber dimensions (fibers > f 20 µm): GMD 0.92 µm and GML 30.2 µm	Male Wistar rats; 6 hr/d, 5 d/wk for 3 mo. Gravimetric exposure: 150 f/ml, 38 mg/m^3; aerosol fibers >20 µm in length: 150 f/ml: GMD 0.88 µm x GML 28.9 µm	No positive control	For fibers >20 µm in length: 0.88 x 10^6; after 3 mo recovery 3.0% remaining. Interstitial fibrosis (EPS score 1)

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