Tissue Burden Results

National Toxicology Program

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National Toxicology Program. NTP Technical Report on the Toxicity Studies of Abrasive Blasting Agents Administered by Inhalation to F344/NTac Rats and Sprague Dawley (Hsd:Sprague Dawley® SD®) Rats: Toxicity Report 91 [Internet]. Research Triangle Park (NC): National Toxicology Program; 2020 Jun.

Cover of NTP Technical Report on the Toxicity Studies of Abrasive Blasting Agents Administered by Inhalation to F344/NTac Rats and Sprague Dawley (Hsd:Sprague Dawley® SD®) Rats

NTP Technical Report on the Toxicity Studies of Abrasive Blasting Agents Administered by Inhalation to F344/NTac Rats and Sprague Dawley (Hsd:Sprague Dawley^® SD^®) Rats: Toxicity Report 91 [Internet].

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Appendix BTissue Burden Results

B.1. Lung Deposition and Clearance Equations Used in the Two-week Inhalation Studies of Abrasive Blasting Agents

Lung clearance rates for the abrasive blasting agents blasting sand, coal slag, crushed glass, garnet, or specular hematite were calculated using Equation (1):

Equation (1): A(t) = A₀(e^−kt)

where A_(t) is the lung burden (μg abrasive blasting agents) at time t (t = 21 days postexposure), A₀ is the lung burden at t = 0 days postexposure (day 16), and k is the lung clearance rate constant (fraction cleared per day). Lung burdens for the specular hematite study were all control corrected.

Lung clearance half-lives in days (t_½) were calculated from Equation (2), where ln2 is the Naperian logarithm of 2:

Equation (2): t_1/2 = ln2/k

Deposition rates were calculated from lung abrasive blasting agent burdens using Equation (3). The lung burden and time at terminal euthanasia and the calculated lung clearance rate constant were used to solve for the deposition rate α (μg/day).

Equation (3): A(t) = (α/k)(1 − e^−kt)

In Equation (3), A(t) is the lung burden (μg abrasive blasting agents) at time t [t = 16 days on study]; α is the amount of abrasive blasting agents deposited (μg/day); and k is the first-order clearance rate constant derived from Equation (1). Steady-state or equilibrium lung burdens (A_e, μg abrasive blasting agents) were calculated according to Equation (4):

Equation (4): A_e = α/k

B.2. Lung Deposition and Clearance Equations Used in the 39-week Inhalation Studies of Abrasive Blasting Agents

The lung burden model used for these studies assumed a zero-order (constant) deposition rate and a first-order (with respect to lung burden) clearance rate as shown in Equation (5):

Equation (5): L_(t) = (D/k)(1 − e^−kt)

In Equation (5), L(t) is the retained abrasive blasting agents lung burden (μg/lung) at any time t (days on study); D is the deposition rate (μg/day); and k is the lung clearance rate constant (days⁻¹). Equation (5) also contains a boundary condition that at t = 0, the mass of abrasive blasting agents in the lung is zero. Lung burdens for the specular hematite study were all control corrected.

This model was fit to the abrasive blasting agents’ lung burden data collected during the in-life part of the 39-week studies. The model was fit to the individual animal data from each exposure group using SAS PROCNLIN (SAS Institute Inc., Cary, NC). Due to the potential for more uncertainty with relatively higher lung burdens, several weighting schemes were investigated, including unweighted, 1/variance, 1/square root of the variance, and bounding permissible estimate of k to greater than zero. Review of the results suggested that 1/square root of the variance was the best choice, so all results are presented from model fits using this weighting.

This model fit provided direct estimates of D and k along with their standard errors for each exposure group. Parameters estimated by the model fit were used to calculate the lung clearance half-time (t_1/2, days) and the theoretical steady-state lung burden (L_ss, μg abrasive blasting agents) for each exposure group along with their standard errors using propagation of error techniques and Equations (6) and (7), respectively:

Equation (6): t_½ = ln2/k

Equation (7): L_ss = D/k

The total lung dose (mg/lung) administered in each exposure group was calculated using Equation (8):

Equation (8): Total dose = 271 × D/1,000

In Equation (8), 271 is the total number of study days; D is the deposition rate (μg/day); and dividing by 1,000 converts units from μg to mg. Also determined for each exposure group was the total amount of abrasive blasting agents cleared from the lungs during the studies, calculated as the difference between the calculated dose and the calculated lung burden at study day 271. This was expressed as both an absolute value and as the percentage relative to the total dose.

B.3. Lung Overload Evaluation Used in the 39-week Inhalation Studies of Abrasive Blasting Agents

Calculations were undertaken to investigate the possibility that lung overload may have occurred in one or more of the exposure groups during the 39-week studies. Calculated lung burdens were converted to the equivalent volume of the abrasive blasting agents and compared to the respective threshold volume required to reach overload.

Using Equation (9), the total volume (μm³) of abrasive blasting agents in the lungs for each day on study was calculated:

Equation (9): V_p(t) = [10⁻³ × L(t)/p] × (10¹²)

In Equation (9), V_p(t) is the volume of the retained lung burden in μm³ at any time t (days on study), L(t) is the calculated lung burden (converted to mg by multiplying by 10⁻³ mg/μg) at time t, p is the density of the abrasive blasting agents (4,990 mg/cm³ or 2,780 mg/cm³ for specular hematite or blasting sand, respectively), and the factor 10¹² converts cm³ to μm³.

Through an iterative calculation using Equation (10), the ratios of the volume of retained abrasive blasting agents’ lung burden at time t [V_p(t)] to the threshold volume required for the onset of lung overload (V*) were determined:

Equation (10): R(t) = V_p(t)/V*

The calculated ratios were used to determine the time of onset of lung overload and the extent of overload achieved over the course of the studies. The time of onset of the overload condition (t*, days) was determined as the earliest time (days on study) for which R(t) > 1.0. The maximum value of the ratio (R_max) was used to determine the extent of overload that occurred by the end of the study (day 271).

Table B-1Lung Weights and Lung Burdens for Male F344/NTac Rats in the Two-week Inhalation Study of Blasting Sand

	Chamber Control		3 mg/m³	15 mg/m³	30 mg/m³
n	5		5	5	5
Absolute Lung Wt. (g)
Day 1		0.59 ± 0.04	0.54 ± 0.01	0.55 ± 0.01	0.56 ± 0.02
Day 5		0.70 ± 0.06	0.64 ± 0.03	0.58 ± 0.01	0.66 ± 0.02
Day 8		0.78 ± 0.04	0.73 ± 0.01	0.68 ± 0.03	0.71 ± 0.04
Day 12		0.77 ± 0.03	0.77 ± 0.01	0.91 ± 0.07	0.82 ± 0.05
Day 15		0.76 ± 0.04	0.85 ± 0.04	0.81 ± 0.07	0.82 ± 0.06
Day 16		0.94 ± 0.05	0.89 ± 0.07	0.93 ± 0.06	0.86 ± 0.05^a
Day 37		0.99 ± 0.04	1.12 ± 0.06	1.00 ± 0.04	1.03 ± 0.04
μg Si/g Lung
Day 1		0.6 ± 0.0	6.9 ± 0.6**	32.9 ± 0.8**	68.2 ± 3.1**
Day 5		0.6 ± 0.0	33.4 ± 1.1**	156.5 ± 3.7**	277.4 ± 10.0**
Day 8		1.0 ± 0.3	28.0 ± 1.4**	124.0 ± 8.7**	245.3 ± 18.0**
Day 12		0.7 ± 0.1	52.1 ± 3.0**	210.8 ± 13.4**	464.0 ± 27.6**
Day 15		0.6 ± 0.0	43.1 ± 3.0**	203.0 ± 19.6**	401.9 ± 28.7**
Day 16		0.7 ± 0.1	48.9 ± 2.8**	228.9 ± 13.4**	526.7 ± 24.9**^a
Day 37		0.8 ± 0.2	33.3 ± 4.0**	136.9 ± 5.6**	280.6 ± 23.1**
μg Si/Total Lung
Day 1		0.4 ± 0.0	3.7 ± 0.3**	18.2 ± 0.6**	38.3 ± 1.7**
Day 5		0.4 ± 0.0	21.4 ± 1.0**	90.8 ± 3.4**	183.9 ± 7.6**
Day 8		0.8 ± 0.2	20.5 ± 0.8**	83.1 ± 3.6**	170.4 ± 5.2**
Day 12		0.6 ± 0.1	40.2 ± 2.0**	188.8 ± 5.0**	377.0 ± 13.8**
Day 15		0.5 ± 0.0	36.1 ± 1.4**	159.3 ± 5.8**	322.8 ± 5.7**
Day 16		0.7 ± 0.1	43.3 ± 2.7**	208.9 ± 5.8**	444.8 ± 8.0**^a
Day 37		0.8 ± 0.2	36.9 ± 3.5**	137.1 ± 6.2**	285.2 ± 20.4**
μg Blasting Sand/g Lung
Day 1		1.5 ± 0.0	17.5 ± 1.5**	83.6 ± 2.1**	173.0 ± 7.9**
Day 5		1.5 ± 0.0	84.8 ± 2.7**	397.3 ± 9.5**	704.2 ± 25.3**
Day 8		2.6 ± 0.6	71.2 ± 3.7**	314.7 ± 22.2**	622.6 ± 45.6**
Day 12		1.8 ± 0.3	132.2 ± 7.6**	535.1 ± 34.0**	1,177.8 ± 70.1**
Day 15		1.5 ± 0.0	109.5 ± 7.5**	515.4 ± 49.7**	1,020.1 ± 72.9**
Day 16		1.8 ± 0.3	124.1 ± 7.1**	581.0 ± 34.0**	1,336.9 ± 63.1**^a
Day 37		2.0 ± 0.5	84.6 ± 10.1**	347.5 ± 14.2**	712.1 ± 58.6**
μg Blasting Sand/Total Lung
Day 1		0.9 ± 0.1	9.4 ± 0.7**	46.2 ± 1.6**	97.1 ± 4.3**
Day 5		1.0 ± 0.1	54.4 ± 2.5**	230.4 ± 8.6**	466.6 ± 19.3**
Day 8		2.0 ± 0.6	52.0 ± 1.9**	210.9 ± 9.2**	432.6 ± 13.3**
Day 12		1.4 ± 0.2	102.1 ± 5.2**	479.1 ± 12.6**	956.9 ± 35.0**
Day 15		1.1 ± 0.1	91.7 ± 3.5**	404.2 ± 14.7**	819.3 ± 14.4**
Day 16		1.7 ± 0.2	109.8 ± 7.0**	530.2 ± 14.8**	1,128.8 ± 20.4**^a
Day 37		2.0 ± 0.6	93.8 ± 8.9**	347.9 ± 15.8**	723.9 ± 51.8**
μg Blasting Sand/g Lung per mg Blasting Sand/m³
Day 1		NA	5.8 ± 0.5	5.6 ± 0.1	5.8 ± 0.3
Day 5		NA	28.3 ± 0.9	26.5 ± 0.6	23.5 ± 0.8
Day 8		NA	23.7 ± 1.2	21.0 ± 1.5	20.8 ± 1.5
Day 12		NA	44.1 ± 2.5	35.7 ± 2.3	39.3 ± 2.3
Day 15		NA	36.5 ± 2.5	34.4 ± 3.3	34.0 ± 2.4
Day 16		NA	41.4 ± 2.4	38.7 ± 2.3	44.6 ± 2.1^a
Day 37		NA	28.2 ± 3.4	23.2 ± 0.9	23.7 ± 2.0
μg Blasting Sand/Total Lung per mg Blasting Sand/m³
Day 1		NA	3.1 ± 0.2	3.1 ± 0.1	3.2 ± 0.1
Day 5		NA	18.1 ± 0.8	15.4 ± 0.6	15.6 ± 0.6
Day 8		NA	17.3 ± 0.6	14.1 ± 0.6	14.4 ± 0.4
Day 12		NA	34.0 ± 1.7	31.9 ± 0.8	31.9 ± 1.2
Day 15		NA	30.6 ± 1.2	26.9 ± 1.0	27.3 ± 0.5
Day 16		NA	36.6 ± 2.3	35.3 ± 1.0	37.6 ± 0.7^a
Day 37		NA	31.3 ± 3.0	23.2 ± 1.1	24.1 ± 1.7

**: Significantly different (p ≤ 0.01) from the chamber control group by Shirley’s test.
: Data are presented as mean ± standard error. Days 1, 5, 12, and 16 were after the daily exposure, days 8 and 15 were before the daily exposure, and day 37 was after 21 days of recovery. For values reported as below the limit of quantification, the values shown are the constant of half the limit of quantification. Statistical tests were performed only on data that were not exposure concentration normalized.
: NA = not applicable.
^a: n = 4.

Table B-2Lymph Node Weights for Male F344/NTac Rats in the Two-week Inhalation Study of Blasting Sand

	Chamber Control		3 mg/m³	15 mg/m³	30 mg/m³
n	5		5	5	5
Bronchial Lymph Node (g)
Day 1		0.010 ± 0.002	0.011 ± 0.003	0.013 ± 0.002	0.010 ± 0.001
Day 5		0.017 ± 0.009	0.013 ± 0.001	0.007 ± 0.000	0.015 ± 0.002
Day 8		0.012 ± 0.002	0.015 ± 0.003	0.012 ± 0.003	0.011 ± 0.002
Day 12		0.011 ± 0.001	0.011 ± 0.001	0.017 ± 0.002	0.015 ± 0.004
Day 15		0.018 ± 0.003	0.011 ± 0.001	0.011 ± 0.001	0.016 ± 0.005
Day 16		0.016 ± 0.004	0.017 ± 0.004	0.017 ± 0.003	0.016 ± 0.004
Day 37		0.017 ± 0.003	0.028 ± 0.004	0.018 ± 0.004	0.025 ± 0.005
Mediastinal Lymph Node (g)
Day 1		0.037 ± 0.020	0.017 ± 0.002	0.019 ± 0.003	0.015 ± 0.003
Day 5		0.022 ± 0.004	0.023 ± 0.004	0.024 ± 0.003	0.025 ± 0.005
Day 8		0.026 ± 0.003	0.027 ± 0.003	0.025 ± 0.006	0.023 ± 0.003
Day 12		0.039 ± 0.011	0.035 ± 0.005	0.032 ± 0.002	0.035 ± 0.006
Day 15		0.035 ± 0.006	0.026 ± 0.006	0.029 ± 0.003	0.029 ± 0.004
Day 16		0.045 ± 0.008	0.035 ± 0.003	0.038 ± 0.003	0.041 ± 0.005
Day 37		0.052 ± 0.003	0.067 ± 0.009	0.057 ± 0.002	0.066 ± 0.004

: Data are presented as mean ± standard error. Days 1, 5, 12, and 16 were after the daily exposure, days 8 and 15 were before the daily exposure, and day 37 was after 21 days of recovery. Differences from the chamber control group are not significant by Dunnett’s test.

Table B-3Lung Deposition and Clearance Parameter Estimates for Male F344/NTac Rats in the Two-week Inhalation Study of Blasting Sand

Parameter	3 mg/m³	15 mg/m³	30 mg/m³
k (days⁻¹)	0.007	0.020	0.021
t_1/2 (days)	93	35	33
α (μg blasting sand/total lung per day)	7	39	83
A_e (μg blasting sand/total lung)	975	1,933	3,931

: Data are presented as group mean values.
: k = first-order lung clearance rate constant; t_1/2 = clearance half-life; α = deposition rate; A_e = steady-state lung burden.

Table B-4Lung Weights and Lung Burdens for Male F344/NTac Rats in the Two-week Inhalation Study of Coal Slag

	Chamber Control		3 mg/m³	15 mg/m³	30 mg/m³
n	5		5	5	5
Absolute Lung Wt. (g)
Day 1		0.56 ± 0.11	0.50 ± 0.02	0.56 ± 0.04	0.54 ± 0.04
Day 5		0.64 ± 0.06	0.64 ± 0.04	0.68 ± 0.04	0.65 ± 0.04
Day 8		0.84 ± 0.01	0.71 ± 0.05	0.75 ± 0.07	0.80 ± 0.10
Day 12		0.77 ± 0.10	0.82 ± 0.05	0.85 ± 0.03	0.83 ± 0.08
Day 15		0.89 ± 0.09	0.84 ± 0.04	0.94 ± 0.06	0.88 ± 0.04
Day 16		0.73 ± 0.02	0.73 ± 0.04	0.79 ± 0.03	0.88 ± 0.06*
Day 37		1.03 ± 0.04	1.01 ± 0.08	1.16 ± 0.05	1.20 ± 0.06
μg Si/g Lung
Day 1		0.6 ± 0.0	0.9 ± 0.3	13.8 ± 1.5**	30.9 ± 2.0**
Day 5		0.6 ± 0.0	16.4 ± 0.7**	69.5 ± 3.2**	115.3 ± 5.6**
Day 8		0.6 ± 0.0	13.8 ± 1.1**	60.1 ± 5.0**	91.4 ± 11.2**
Day 12		0.6 ± 0.0	25.0 ± 1.5**	112.4 ± 2.2**	200.1 ± 15.2**
Day 15		0.6 ± 0.0	21.8 ± 1.7**	93.9 ± 7.9**	176.0 ± 4.6**
Day 16		0.6 ± 0.0	35.2 ± 2.1**	146.7 ± 5.6**	240.6 ± 14.4**
Day 37		0.6 ± 0.0	18.5 ± 1.7**	77.7 ± 4.2**	142.4 ± 8.1**
μg Si/Total Lung
Day 1		0.3 ± 0.1	0.4 ± 0.1	7.6 ± 0.8**	16.3 ± 0.7**
Day 5		0.4 ± 0.0	10.3 ± 0.2**	46.9 ± 1.8**	74.6 ± 2.1**
Day 8		0.5 ± 0.1	9.5 ± 0.1**	43.6 ± 0.9**	69.7 ± 5.0**
Day 12		0.5 ± 0.1	20.1 ± 0.4**	94.9 ± 1.6**	160.8 ± 3.3**
Day 15		0.5 ± 0.1	18.2 ± 1.2**	86.8 ± 2.2**	155.0 ± 3.3**
Day 16		0.4 ± 0.0	25.5 ± 0.8**	115.1 ± 3.6**	209.9 ± 9.3**
Day 37		0.6 ± 0.0	18.3 ± 1.0**	89.2 ± 1.3**	169.5 ± 5.4**
μg Coal Slag/g Lung
Day 1		2.8 ± 0.0	4.0 ± 1.2	63.4 ± 6.9**	141.5 ± 9.0**
Day 5		2.8 ± 0.0	75.0 ± 3.2**	318.8 ± 14.8**	529.0 ± 25.6**
Day 8		2.8 ± 0.0	63.1 ± 5.0**	275.7 ± 22.9**	419.1 ± 51.3**
Day 12		2.8 ± 0.0	114.7 ± 6.9**	515.8 ± 10.0**	917.9 ± 69.7**
Day 15		2.8 ± 0.0	100.1 ± 7.6**	430.7 ± 36.0**	807.2 ± 21.0**
Day 16		2.8 ± 0.0	161.7 ± 9.6**	672.8 ± 25.9**	1,103.6 ± 65.9**
Day 37		2.8 ± 0.0	84.7 ± 7.8**	356.6 ± 19.1**	653.3 ± 37.1**
μg Coal Slag/Total Lung
Day 1		1.5 ± 0.3	1.9 ± 0.6	34.9 ± 3.7**	74.7 ± 3.3**
Day 5		1.8 ± 0.2	47.4 ± 1.1**	215.3 ± 8.2**	342.2 ± 9.7**
Day 8		2.3 ± 0.3	43.6 ± 0.5**	199.9 ± 3.9**	319.8 ± 22.7**
Day 12		2.1 ± 0.3	92.2 ± 1.6**	435.2 ± 7.5**	737.6 ± 15.3**
Day 15		2.5 ± 0.3	83.6 ± 5.5**	398.0 ± 10.1**	710.9 ± 15.1**
Day 16		2.0 ± 0.1	116.9 ± 3.9**	528.2 ± 16.4**	962.8 ± 42.8**
Day 37		2.8 ± 0.1	83.7 ± 4.8**	409.4 ± 6.1**	777.5 ± 24.7**
μg Coal Slag/g Lung per mg Coal Slag/m³
Day 1		NA	1.3 ± 0.4	4.2 ± 0.5	4.7 ± 0.3
Day 5		NA	25.0 ± 1.1	21.3 ± 1.0	17.6 ± 0.9
Day 8		NA	21.0 ± 1.7	18.4 ± 1.5	14.0 ± 1.7
Day 12		NA	38.2 ± 2.3	34.4 ± 0.7	30.6 ± 2.3
Day 15		NA	33.4 ± 2.5	28.7 ± 2.4	26.9 ± 0.7
Day 16		NA	53.9 ± 3.2	44.9 ± 1.7	36.8 ± 2.2
Day 37		NA	28.2 ± 2.6	23.8 ± 1.3	21.8 ± 1.2
μg Coal Slag/Total Lung per mg Coal Slag/m³
Day 1		NA	0.6 ± 0.2	2.3 ± 0.3	2.5 ± 0.1
Day 5		NA	15.8 ± 0.4	14.4 ± 0.6	11.4 ± 0.3
Day 8		NA	14.6 ± 0.2	13.3 ± 0.3	10.7 ± 0.8
Day 12		NA	30.7 ± 0.5	29.0 ± 0.5	24.6 ± 0.5
Day 15		NA	27.9 ± 1.8	26.5 ± 0.7	23.7 ± 0.5
Day 16		NA	39.0 ± 1.3	35.2 ± 1.1	32.1 ± 1.4
Day 37		NA	27.9 ± 1.6	27.3 ± 0.4	25.9 ± 0.8

**: Significantly different (p ≤ 0.01) from the chamber control group by Shirley’s test.
: Data are presented as mean ± standard error. Days 1, 5, 12, and 16 were after the daily exposure, days 8 and 15 were before the daily exposure, and day 37 was after 21 days of recovery. For values reported as below the limit of quantification, the values shown are the constant of half the limit of quantification. Statistical tests were performed only on data that were not exposure concentration normalized.
: NA = not applicable.

Table B-5Lymph Node Weights for Male F344/NTac Rats in the Two-week Inhalation Study of Coal Slag

	Chamber Control		3 mg/m³	15 mg/m³	30 mg/m³
n	5		5	5	5
Bronchial Lymph Node (g)
Day 1		0.006 ± 0.002	0.004 ± 0.001	0.006 ± 0.001	0.004 ± 0.002
Day 5		0.005 ± 0.002	0.006 ± 0.003	0.006 ± 0.003	0.006 ± 0.003
Day 8		0.006 ± 0.003	0.006 ± 0.002	0.009 ± 0.004	0.006 ± 0.004
Day 12		0.007 ± 0.002	0.009 ± 0.003	0.017 ± 0.011	0.009 ± 0.006
Day 15		0.012 ± 0.003	0.013 ± 0.009	0.012 ± 0.005	0.010 ± 0.003
Day 16		0.010 ± 0.003	0.012 ± 0.003	0.010 ± 0.004	0.016 ± 0.012
Day 37		0.023 ± 0.002	0.025 ± 0.032	0.032 ± 0.019	0.035 ± 0.024
Mediastinal Lymph Node (g)
Day 1		0.027 ± 0.009	0.029 ± 0.011	0.030 ± 0.006	0.031 ± 0.010
Day 5		0.031 ± 0.004	0.032 ± 0.012	0.033 ± 0.007	0.031 ± 0.007
Day 8		0.025 ± 0.007	0.038 ± 0.004	0.037 ± 0.003	0.039 ± 0.021
Day 12		0.038 ± 0.002	0.041 ± 0.011	0.046 ± 0.010	0.051 ± 0.010
Day 15		0.048 ± 0.010	0.046 ± 0.011	0.050 ± 0.018	0.045 ± 0.017
Day 16		0.042 ± 0.009	0.035 ± 0.007	0.033 ± 0.006	0.039 ± 0.006
Day 37		0.065 ± 0.022	0.065 ± 0.026	0.068 ± 0.026	0.076 ± 0.013

: Data are presented as mean ± standard error. Days 1, 5, 12, and 16 were after the daily exposure, days 8 and 15 were before the daily exposure, and day 37 was after 21 days of recovery. Differences from the chamber control group are not significant by Dunnett’s test.

Table B-6Lung Deposition and Clearance Parameter Estimates for Male F344/NTac Rats in the Two-week Inhalation Study of Coal Slag

Parameter	3 mg/m³	15 mg/m³	30 mg/m³
k (days⁻¹)	0.016	0.012	0.010
t_1/2 (days)	44	57	68
α (μg coal slag/total lung per day)	8	36	65
A_e (μg coal slag/total lung)	524	2,986	6,419

: Data are presented as group mean values.
: k = first-order lung clearance rate constant; t_1/2 = clearance half-life; α = deposition rate; A_e = steady-state lung burden.

Table B-7Lung Weights and Lung Burdens for Male F344/NTac Rats in the Two-week Inhalation Study of Crushed Glass

	Chamber Control		3 mg/m³	15 mg/m³	30 mg/m³
n	5		5	5	5
Absolute Lung Wt. (g)
Day 1		0.63 ± 0.06	0.52 ± 0.03	0.54 ± 0.03	0.50 ± 0.01
Day 5		0.62 ± 0.02	0.64 ± 0.02	0.61 ± 0.01	0.61 ± 0.02
Day 8		0.83 ± 0.04	0.72 ± 0.05	0.79 ± 0.06	0.70 ± 0.03
Day 12		0.80 ± 0.04	0.81 ± 0.04	0.79 ± 0.02	0.80 ± 0.06
Day 15		0.90 ± 0.08	0.89 ± 0.04	0.91 ± 0.06	0.92 ± 0.06
Day 16		0.88 ± 0.04	0.92 ± 0.08	0.82 ± 0.02	0.86 ± 0.04
Day 37		1.19 ± 0.07	1.20 ± 0.05	1.12 ± 0.06	1.04 ± 0.03
μg Si/g Lung
Day 1		0.6 ± 0.0	1.6 ± 0.8	15.1 ± 1.0**	34.7 ± 2.0**
Day 5		0.6 ± 0.0	6.8 ± 0.4**	54.1 ± 2.5**	95.9 ± 3.2**
Day 8		0.6 ± 0.0	8.7 ± 0.6**	38.3 ± 3.4**	82.6 ± 5.3**
Day 12		0.6 ± 0.0	18.9 ± 0.8**	90.2 ± 3.1**	172.9 ± 9.3**
Day 15		0.6 ± 0.0	13.2 ± 1.1**	70.4 ± 2.5**	126.4 ± 7.7**
Day 16		0.6 ± 0.0	19.2 ± 1.9**	108.2 ± 5.5**	188.3 ± 14.5**
Day 37		0.6 ± 0.0	3.1 ± 0.4**	32.7 ± 1.9**	62.8 ± 1.0**
μg Si/Total Lung
Day 1		0.4 ± 0.0	0.9 ± 0.4	8.1 ± 0.5**	17.5 ± 1.2**
Day 5		0.4 ± 0.0	4.3 ± 0.3**	33.0 ± 1.8**	58.8 ± 3.1**
Day 8		0.5 ± 0.0	6.2 ± 0.2**	29.3 ± 0.7**	57.3 ± 2.8**
Day 12		0.5 ± 0.0	15.3 ± 0.8**	71.3 ± 2.5**	136.1 ± 3.8**
Day 15		0.5 ± 0.1	11.6 ± 0.4**	63.2 ± 2.7**	114.4 ± 2.5**
Day 16		0.5 ± 0.0	17.0 ± 0.9**	88.5 ± 4.7**	159.9 ± 7.5**
Day 37		0.7 ± 0.0	3.7 ± 0.6**	37.1 ± 4.0**	65.3 ± 2.6**
μg Crushed Glass/g Lung
Day 1		1.9 ± 0.0	5.1 ± 2.5	48.3 ± 3.2**	111.2 ± 6.4**
Day 5		1.9 ± 0.0	21.7 ± 1.3**	173.3 ± 8.0**	307.3 ± 10.3**
Day 8		1.9 ± 0.0	27.7 ± 1.8**	122.6 ± 10.8**	264.9 ± 17.0**
Day 12		1.9 ± 0.0	60.5 ± 2.7**	289.0 ± 9.8**	554.1 ± 29.8**
Day 15		1.9 ± 0.0	42.4 ± 3.6**	225.6 ± 8.1**	405.2 ± 24.8**
Day 16		1.9 ± 0.0	61.4 ± 6.2**	346.9 ± 17.6**	603.6 ± 46.3**
Day 37		1.9 ± 0.0	9.9 ± 1.4**	104.7 ± 6.1**	201.3 ± 3.2**
μg Crushed Glass/Total Lung
Day 1		1.2 ± 0.1	2.7 ± 1.4	26.0 ± 1.6**	56.1 ± 4.0**
Day 5		1.2 ± 0.0	13.8 ± 1.0**	105.9 ± 5.6**	188.6 ± 10.0**
Day 8		1.6 ± 0.1	19.7 ± 0.6**	93.9 ± 2.1**	183.6 ± 9.0**
Day 12		1.5 ± 0.1	49.0 ± 2.7**	228.6 ± 7.9**	436.2 ± 12.3**
Day 15		1.7 ± 0.2	37.1 ± 1.2**	202.6 ± 8.5**	366.7 ± 8.1**
Day 16		1.7 ± 0.1	54.6 ± 2.7**	283.5 ± 15.1**	512.5 ± 23.9**
Day 37		2.3 ± 0.1	11.9 ± 1.9**	118.8 ± 12.9**	209.4 ± 8.4**
μg Crushed Glass/g Lung per mg Crushed Glass/m³
Day 1		NA	1.7 ± 0.8	3.2 ± 0.2	3.7 ± 0.2
Day 5		NA	7.2 ± 0.4	11.6 ± 0.5	10.2 ± 0.3
Day 8		NA	9.3 ± 0.6	8.2 ± 0.7	8.8 ± 0.6
Day 12		NA	20.2 ± 0.9	19.3 ± 0.7	18.5 ± 1.0
Day 15		NA	14.1 ± 1.2	15.0 ± 0.5	13.5 ± 0.8
Day 16		NA	20.5 ± 2.1	23.1 ± 1.2	20.1 ± 1.5
Day 37		NA	3.3 ± 0.5	7.0 ± 0.4	6.7 ± 0.1
μg Crushed Glass/Total Lung per mg Crushed Glass/m³
Day 1		NA	0.9 ± 0.5	1.7 ± 0.1	1.9 ± 0.1
Day 5		NA	4.6 ± 0.3	7.1 ± 0.4	6.3 ± 0.3
Day 8		NA	6.6 ± 0.2	6.3 ± 0.1	6.1 ± 0.3
Day 12		NA	16.3 ± 0.9	15.2 ± 0.5	14.5 ± 0.4
Day 15		NA	12.4 ± 0.4	13.5 ± 0.6	12.2 ± 0.3
Day 16		NA	18.2 ± 0.9	18.9 ± 1.0	17.1 ± 0.8
Day 37		NA	4.0 ± 0.7	7.9 ± 0.9	7.0 ± 0.3

**: Significantly different (p ≤ 0.01) from the chamber control group by Shirley’s test.
: Data are presented as mean ± standard error. Days 1, 5, 12, and 16 were after the daily exposure, days 8 and 15 were before the daily exposure, and day 37 was after 21 days of recovery. For values reported as below the limit of quantification, the values shown are the constant of half the limit of quantification. Statistical tests were performed only on data that were not exposure concentration normalized.
: NA = not applicable.

Table B-8Lymph Node Weights for Male F344/NTac Rats in the Two-week Inhalation Study of Crushed Glass

	Chamber Control		3 mg/m³	15 mg/m³	30 mg/m³
n	5		5	5	5
Bronchial Lymph Node (g)
Day 1		0.015 ± 0.004	0.012 ± 0.005	0.010 ± 0.004	0.011 ± 0.004
Day 5		0.011 ± 0.004	0.011 ± 0.002	0.012 ± 0.005	0.012 ± 0.006
Day 8		0.016 ± 0.005	0.015 ± 0.005	0.014 ± 0.008	0.016 ± 0.006
Day 12		0.014 ± 0.001	0.012 ± 0.007	0.019 ± 0.015	0.011 ± 0.002
Day 15		0.012 ± 0.004	0.010 ± 0.006	0.014 ± 0.002	0.015 ± 0.006
Day 16		0.018 ± 0.005	0.013 ± 0.005	0.013 ± 0.003	0.016 ± 0.005
Day 37		0.023 ± 0.005	0.023 ± 0.004	0.018 ± 0.009	0.020 ± 0.005
Mediastinal Lymph Node (g)
Day 1		0.023 ± 0.004	0.025 ± 0.003	0.021 ± 0.003	0.024 ± 0.005
Day 5		0.023 ± 0.005	0.028 ± 0.003	0.027 ± 0.007	0.020 ± 0.004
Day 8		0.025 ± 0.001	0.034 ± 0.004	0.029 ± 0.009	0.032 ± 0.009
Day 12		0.030 ± 0.005	0.031 ± 0.008	0.026 ± 0.007	0.032 ± 0.005
Day 15		0.037 ± 0.006	0.040 ± 0.009	0.039 ± 0.003	0.037 ± 0.007
Day 16		0.030 ± 0.008	0.028 ± 0.002	0.032 ± 0.009	0.032 ± 0.010
Day 37		0.056 ± 0.013	0.049 ± 0.006	0.061 ± 0.020	0.059 ± 0.008

: Data are presented as mean ± standard error. Days 1, 5, 12, and 16 were after the daily exposure, days 8 and 15 were before the daily exposure, and day 37 was after 21 days of recovery. Differences from the chamber control group are not significant by the Dunnett test.

Table B-9Lung Deposition and Clearance Parameter Estimates for Male F344/NTac Rats in the Two-week Inhalation Study of Crushed Glass

Parameter	3 mg/m³	15 mg/m³	30 mg/m³
k (days⁻¹)	0.072	0.041	0.043
t_1/2 (days)	10	17	16
α (μg crushed glass/total lung per day)	6	24	44
A_e (μg crushed glass/total lung)	80	586	1,035

: Data are presented as group mean values.
: k = first-order lung clearance rate constant; t_1/2 = clearance half-life; α = deposition rate; A_e = steady-state lung burden.

Table B-10Lung Weights and Lung Burdens for Male F344/NTac Rats in the Two-week Inhalation Study of Garnet

	Chamber Control	3 mg/m³	15 mg/m³	30 mg/m³
n	5	5	5	5
Absolute Lung Wt. (g)
Day 1	0.53 ± 0.02	0.53 ± 0.02	0.56 ± 0.04	0.60 ± 0.02
Day 5	0.63 ± 0.03	0.59 ± 0.01	0.59 ± 0.02	0.63 ± 0.05
Day 8	0.72 ± 0.03	0.71 ± 0.04	0.78 ± 0.05	0.69 ± 0.04
Day 12	0.67 ± 0.03	0.74 ± 0.03	0.80 ± 0.06	0.77 ± 0.03
Day 15	0.75 ± 0.03	0.75 ± 0.04	0.82 ± 0.05	0.84 ± 0.03
Day 16	0.82 ± 0.05	0.81 ± 0.04	0.83 ± 0.02	0.84 ± 0.02
Day 37	1.42 ± 0.28	1.14 ± 0.07	1.31 ± 0.10	1.35 ± 0.07
μg Si/g Lung
Day 1	0.6 ± 0.0	2.6 ± 0.3**	15.2 ± 1.2**	26.2 ± 1.0**
Day 5	0.6 ± 0.0	15.0 ± 0.6**	68.0 ± 3.5**	115.7 ± 4.9**
Day 8	0.6 ± 0.0	10.5 ± 0.4**	50.2 ± 2.6**	100.9 ± 5.1**
Day 12	0.6 ± 0.0	25.3 ± 0.8**	110.4 ± 8.0**	204.7 ± 11.8**
Day 15	0.6 ± 0.0	20.1 ± 1.5**	96.7 ± 2.6**	168.2 ± 4.3**
Day 16	1.1 ± 0.5	26.7 ± 0.6**	119.2 ± 7.7**	213.8 ± 12.6**
Day 37	0.6 ± 0.0	12.6 ± 0.9**	65.5 ± 5.7**	113.6 ± 10.1**
μg Si/Total Lung
Day 1	0.3 ± 0.0	1.4 ± 0.1**	8.3 ± 0.4**	15.6 ± 0.5**
Day 5	0.4 ± 0.0	8.9 ± 0.4**	40.1 ± 2.9**	72.3 ± 3.7**
Day 8	0.4 ± 0.0	7.4 ± 0.3**	38.5 ± 1.5**	68.6 ± 2.6**
Day 12	0.4 ± 0.0	18.7 ± 0.2**	86.9 ± 3.4**	155.9 ± 6.8**
Day 15	0.5 ± 0.0	15.2 ± 1.6**	78.3 ± 2.8**	140.3 ± 5.6**
Day 16	0.8 ± 0.3	21.6 ± 0.9**	99.1 ± 7.1**	178.0 ± 8.5**
Day 37	0.9 ± 0.2	14.2 ± 0.6**	84.2 ± 4.9**	151.2 ± 9.8**
μg Garnet/g Lung
Day 1	3.6 ± 0.0	15.3 ± 1.6**	91.0 ± 7.2**	157.0 ± 5.7**
Day 5	3.6 ± 0.0	90.0 ± 3.6**	406.9 ± 21.0**	692.7 ± 29.4**
Day 8	3.6 ± 0.0	62.6 ± 2.3**	300.3 ± 15.6**	604.4 ± 30.3**
Day 12	3.6 ± 0.0	151.4 ± 4.7**	660.8 ± 47.7**	1,225.6 ± 70.4**
Day 15	3.6 ± 0.0	120.1 ± 8.9**	579.0 ± 15.5**	1,007.1 ± 25.7**
Day 16	6.6 ± 3.0	160.0 ± 3.3**	713.9 ± 46.3**	1,280.2 ± 75.6**
Day 37	3.6 ± 0.0	75.5 ± 5.2**	392.5 ± 34.1**	680.4 ± 60.4**
μg Garnet/Total Lung
Day 1	1.9 ± 0.1	8.1 ± 0.8**	49.6 ± 2.4**	93.4 ± 2.9**
Day 5	2.3 ± 0.1	53.4 ± 2.2**	240.0 ± 17.5**	432.8 ± 22.1**
Day 8	2.6 ± 0.1	44.0 ± 1.5**	230.5 ± 8.8**	411.0 ± 15.7**
Day 12	2.4 ± 0.1	111.7 ± 1.0**	520.1 ± 20.4**	933.5 ± 40.7**
Day 15	2.7 ± 0.1	90.8 ± 9.4**	469.0 ± 16.9**	840.4 ± 33.5**
Day 16	5.0 ± 2.0	129.5 ± 5.4**	593.5 ± 42.6**	1,065.8 ± 51.2**
Day 37	5.1 ± 1.0	85.0 ± 3.4**	504.3 ± 29.5**	905.3 ± 58.4**
μg Garnet/g Lung per mg Garnet/m³
Day 1	NA	5.1 ± 0.5	6.1 ± 0.5	5.2 ± 0.2
Day 5	NA	30.0 ± 1.2	27.1 ± 1.4	23.1 ± 1.0
Day 8	NA	20.9 ± 0.8	20.0 ± 1.0	20.2 ± 1.0
Day 12	NA	50.5 ± 1.6	44.1 ± 3.2	40.9 ± 2.4
Day 15	NA	40.0 ± 3.0	38.6 ± 1.0	33.6 ± 0.9
Day 16	NA	53.3 ± 1.1	47.6 ± 3.1	42.7 ± 2.5
Day 37	NA	25.2 ± 1.8	26.2 ± 2.3	22.7 ± 2.0
μg Garnet/Total Lung per mg Garnet/m³
Day 1	NA	2.7 ± 0.3	3.3 ± 0.2	3.1 ± 0.1
Day 5	NA	17.8 ± 0.8	16.0 ± 1.2	14.4 ± 0.7
Day 8	NA	14.7 ± 0.5	15.4 ± 0.6	13.7 ± 0.5
Day 12	NA	37.2 ± 0.3	34.7 ± 1.4	31.1 ± 1.4
Day 15	NA	30.3 ± 3.1	31.3 ± 1.1	28.0 ± 1.1
Day 16	NA	43.2 ± 1.8	39.6 ± 2.8	35.5 ± 1.7
Day 37	NA	28.3 ± 1.1	33.6 ± 2.0	30.2 ± 2.0

**: Significantly different (p ≤ 0.01) from the chamber control group by Shirley’s test.
: Data are presented as mean ± standard error. Days 1, 5, 12, and 16 were after the daily exposure, days 8 and 15 were before the daily exposure, and day 37 was after 21 days of recovery. For values reported as below the limit of quantification, the values shown are the constant of half the limit of quantification. Statistical tests were performed only on data that were not exposure concentration normalized.
: NA = not applicable.

Table B-11Lymph Node Weights for Male F344/NTac Rats in the Two-week Inhalation Study of Garnet

	Chamber Control		3 mg/m³	15 mg/m³	30 mg/m³
n	5		5	5	5
Bronchial Lymph Node (g)
Day 1		0.009 ± 0.002	0.013 ± 0.002	0.011 ± 0.004	0.014 ± 0.005
Day 5		0.012 ± 0.004	0.007 ± 0.003	0.007 ± 0.002	0.010 ± 0.002
Day 8		0.013 ± 0.005	0.013 ± 0.004	0.010 ± 0.003	0.015 ± 0.002
Day 12		0.008 ± 0.002	0.013 ± 0.005*	0.011 ± 0.002	0.014 ± 0.002*
Day 15		0.011 ± 0.005	0.016 ± 0.004	0.013 ± 0.002	0.016 ± 0.003
Day 16		0.012 ± 0.003	0.017 ± 0.009	0.021 ± 0.008	0.013 ± 0.004
Day 37		0.015 ± 0.006	0.016 ± 0.006	0.024 ± 0.012	0.025 ± 0.014
Mediastinal Lymph Node (g)
Day 1		0.015 ± 0.006	0.017 ± 0.006	0.018 ± 0.006	0.017 ± 0.002
Day 5		0.020 ± 0.009	0.019 ± 0.013	0.015 ± 0.007	0.017 ± 0.005
Day 8		0.030 ± 0.007	0.024 ± 0.007	0.028 ± 0.008	0.028 ± 0.006
Day 12		0.037 ± 0.004	0.031 ± 0.005	0.034 ± 0.008	0.029 ± 0.007
Day 15		0.038 ± 0.006	0.043 ± 0.007	0.044 ± 0.004	0.044 ± 0.004
Day 16		0.052 ± 0.014	0.056 ± 0.013	0.051 ± 0.015	0.042 ± 0.017
Day 37		0.055 ± 0.008	0.053 ± 0.003	0.062 ± 0.014	0.063 ± 0.006

*: Significantly different (p ≤ .0.05) from the chamber control group by Dunnett’s test.
: Data are presented as mean ± standard error. Days 1, 5, 12, and 16 were after the daily exposure, days 8 and 15 were before the daily exposure, and day 37 was after 21 days of recovery.

Table B-12Lung Deposition and Clearance Parameter Estimates for Male F344/NTac Rats in the Two-week Inhalation Study of Garnet

Parameter	3 mg/m³	15 mg/m³	30 mg/m³
k (days⁻¹)	0.020	0.008	0.008
t_1/2 (days)	35	90	89
α (μg garnet/total lung per day)	9	39	71
A_e (μg garnet/total lung)	474	5,089	9,089

: Data are presented as group mean values.
: k = first-order lung clearance rate constant; t_1/2 = clearance half-life; α = deposition rate; A_e = steady-state lung burden.

Table B-13Lung Weights and Lung Burdens for Male F344/NTac Rats in the Two-week Inhalation Study of Specular Hematite

	Chamber Control	3 mg/m³	15 mg/m³	30 mg/m³	60 mg/m³
n	5	5	5	5	5
Absolute Lung Wt. (g)
Day 1	0.57 ± 0.03	0.56 ± 0.03	0.58 ± 0.02	0.54 ± 0.02	0.54 ± 0.02
Day 5	0.66 ± 0.05	0.63 ± 0.02	0.64 ± 0.06	0.68 ± 0.04	0.60 ± 0.03
Day 8	0.70 ± 0.03	0.74 ± 0.04	0.69 ± 0.05	0.73 ± 0.05	0.74 ± 0.07
Day 12	0.83 ± 0.06	0.85 ± 0.09	0.72 ± 0.02	0.80 ± 0.05	0.81 ± 0.06
Day 15	0.79 ± 0.03	0.74 ± 0.03	0.81 ± 0.04	0.75 ± 0.04	0.87 ± 0.06
Day 16	0.81 ± 0.04	0.78 ± 0.02	0.87 ± 0.04	0.83 ± 0.11	0.79 ± 0.04
Day 37	0.95 ± 0.04	1.03 ± 0.07	1.01 ± 0.03	1.08 ± 0.02	1.52 ± 0.40*
μg Fe/g Lung
Day 1	48.82 ± 1.32	67.13 ± 3.62**	134.02 ± 8.21**	144.88 ± 4.69**	238.41 ± 7.83**
Day 5	55.22 ± 2.45	124.91 ± 4.50**	362.65 ± 35.17**	504.46 ± 28.72**	916.49 ± 43.84**
Day 8	54.50 ± 4.26	106.30 ± 4.83**	326.25 ± 17.90**	423.97 ± 27.71**	709.69 ± 76.78**
Day 12	54.37 ± 0.59	141.68 ± 9.91**	503.76 ± 14.31**	797.62 ± 68.57**	1,353.0 ± 68.74**
Day 15	64.17 ± 5.51	140.80 ± 4.96**	432.67 ± 27.70**	745.63 ± 28.70**	1,264.5 ± 75.81**
Day 16	54.12 ± 2.99	157.68 ± 4.34**	513.81 ± 17.19**	835.34 ± 50.01**	1,637.9 ± 87.70**
Day 37	68.66 ± 2.24	127.31 ± 4.04**	309.93 ± 13.55**	506.94 ± 19.01**	797.55 ± 142.71**
μg Fe/g Lung (Control Corrected)
Day 1	NA	18.313 ± 3.619	85.200 ± 8.215	96.058 ± 4.693	189.589 ± 7.828
Day 5	NA	69.682 ± 4.497	307.429 ± 35.173	449.239 ± 28.720	861.263 ± 43.842
Day 8	NA	51.801 ± 4.826	271.749 ± 17.904	369.476 ± 27.714	655.194 ± 76.776
Day 12	NA	87.312 ± 9.908	449.385 ± 14.308	743.244 ± 68.574	1,298.65 ± 68.741
Day 15	NA	76.628 ± 4.960	368.499 ± 27.700	681.460 ± 28.705	1,200.33 ± 75.805
Day 16	NA	103.558 ± 4.339	459.688 ± 17.189	781.225 ± 50.009	1,583.73 ± 87.702
Day 37	NA	58.654 ± 4.041	241.275 ± 13.552	438.280 ± 19.014	728.890 ± 142.711
μg Fe/Total Lung (Control Corrected)
Day 1	NA	9.951 ± 1.714	48.450 ± 2.935	51.263 ± 2.529	101.681 ± 3.393
Day 5	NA	43.272 ± 1.878	189.985 ± 9.708	300.703 ± 6.666	514.595 ± 14.909
Day 8	NA	37.465 ± 2.154	184.982 ± 5.977	263.676 ± 9.185	465.181 ± 36.399
Day 12	NA	70.293 ± 1.164	322.883 ± 16.120	582.229 ± 28.068	1,040.18 ± 48.300
Day 15	NA	56.842 ± 3.567	294.985 ± 17.426	508.902 ± 7.167	1,030.47 ± 53.236
Day 16	NA	80.644 ± 3.755	396.829 ± 12.272	630.258 ± 33.507	1,235.45 ± 36.812
Day 37	NA	59.401 ± 3.259	245.654 ± 19.602	470.798 ± 16.954	890.235 ± 115.848
μg Specular Hematite/g Lung (Control Corrected)
Day 1	NA	26.388 ± 5.215	122.767 ± 11.837	138.412 ± 6.762	273.183 ± 11.280
Day 5	NA	100.406 ± 6.479	442.981 ± 50.681	647.319 ± 41.383	1,241.01 ± 63.173
Day 8	NA	74.642 ± 6.954	391.569 ± 25.799	532.386 ± 39.933	944.083 ± 110.628
Day 12	NA	125.810 ± 14.277	647.529 ± 20.617	1,070.96 ± 98.810	1,871.26 ± 99.051
Day 15	NA	110.415 ± 7.147	530.978 ± 39.913	981.930 ± 41.361	1,729.58 ± 109.230
Day 16	NA	149.219 ± 6.252	662.375 ± 24.767	1,125.68 ± 72.059	2,282.04 ± 126.372
Day 37	NA	84.516 ± 5.823	347.659 ± 19.527	631.528 ± 27.398	1,050.27 ± 205.635
μg Specular Hematite/Total Lung (Control Corrected)
Day 1	NA	14.339 ± 2.470	69.813 ± 4.228	73.866 ± 3.644	146.515 ± 4.889
Day 5	NA	62.352 ± 2.706	273.753 ± 13.989	433.290 ± 9.605	741.491 ± 21.482
Day 8	NA	53.984 ± 3.103	266.545 ± 8.612	379.937 ± 13.235	670.290 ± 52.448
Day 12	NA	101.287 ± 1.677	465.250 ± 23.229	838.947 ± 40.443	1,498.82 ± 69.597
Day 15	NA	81.905 ± 5.139	425.051 ± 25.110	733.288 ± 10.326	1,484.83 ± 76.708
Day 16	NA	116.202 ± 5.411	571.799 ± 17.683	908.153 ± 48.281	1,780.18 ± 53.043
Day 37	NA	85.591 ± 4.696	353.968 ± 28.245	678.383 ± 24.429	1,282.76 ± 166.928
μg Specular Hematite/Total Lung per mg Specular Hematite/m³ (Control Corrected)
Day 1	NA	4.780 ± 0.824	4.654 ± 0.282	2.462 ± 0.122	2.442 ± 0.081
Day 5	NA	20.784 ± 0.902	18.250 ± 0.933	14.443 ± 0.320	12.358 ± 0.358
Day 8	NA	17.995 ± 1.034	17.770 ± 0.574	12.665 ± 0.441	11.171 ± 0.874
Day 12	NA	33.763 ± 0.559	31.017 ± 1.549	27.965 ± 1.348	24.980 ± 1.160
Day 15	NA	27.302 ± 1.713	28.337 ± 1.674	24.443 ± 0.344	24.747 ± 1.279
Day 16	NA	38.734 ± 1.804	38.120 ± 1.179	30.272 ± 1.609	29.670 ± 0.884
Day 37	NA	28.531 ± 1.565	23.598 ± 1.883	22.613 ± 0.814	21.379 ± 2.782

*: Significantly different (p ≤ 0.05) from the chamber control group by the Williams or Shirley tests.
**: p ≤ 0.01.
: Data are presented as mean ± standard error. Days 1, 5, 12, and 16 were after the daily exposure, days 8 and 15 were before the daily exposure, and day 37 was after 21 days of recovery. Statistical tests were performed only on data that were not control corrected.
: NA = not applicable.

Table B-14Lymph Node Weights for Male F344/NTac Rats in the Two-week Inhalation Study of Specular Hematite

	Chamber Control	3 mg/m³	15 mg/m³	30 mg/m³	60 mg/m³
n	5	5	5	5	5
Bronchial Lymph Node (g)
Day 1	0.017 ± 0.001	0.016 ± 0.003	0.018 ± 0.002	0.024 ± 0.003	0.021 ± 0.004
Day 5	0.010 ± 0.001	0.008 ± 0.001	0.009 ± 0.002	0.007 ± 0.002	0.008 ± 0.001
Day 8	0.020 ± 0.003	0.023 ± 0.003	0.022 ± 0.003	0.018 ± 0.002	0.025 ± 0.002
Day 12	0.031 ± 0.004	0.015 ± 0.003*	0.023 ± 0.005	0.024 ± 0.003	0.022 ± 0.005
Day 15	0.015 ± 0.004	0.013 ± 0.002	0.012 ± 0.002	0.011 ± 0.001	0.016 ± 0.003
Day 16	0.018 ± 0.003	0.017 ± 0.002	0.015 ± 0.002	0.013 ± 0.001	0.012 ± 0.003
Day 37	0.019 ± 0.003	0.022 ± 0.010	0.033 ± 0.008	0.027 ± 0.003	0.036 ± 0.008
Mediastinal Lymph Node (g)
Day 1	0.025 ± 0.002	0.027 ± 0.002	0.029 ± 0.006	0.030 ± 0.002	0.031 ± 0.003
Day 5	0.026 ± 0.004	0.036 ± 0.003	0.028 ± 0.003	0.026 ± 0.005	0.032 ± 0.004
Day 8	0.038 ± 0.005	0.035 ± 0.002	0.038 ± 0.003	0.035 ± 0.004	0.035 ± 0.002
Day 12	0.027 ± 0.001	0.035 ± 0.002	0.030 ± 0.003	0.039 ± 0.003*	0.028 ± 0.004
Day 15	0.037 ± 0.003	0.040 ± 0.007	0.042 ± 0.004	0.042 ± 0.004	0.045 ± 0.004
Day 16	0.029 ± 0.003	0.031 ± 0.002	0.033 ± 0.004	0.034 ± 0.005	0.030 ± 0.003
Day 37	0.056 ± 0.006	0.062 ± 0.008	0.057 ± 0.005	0.050 ± 0.003	0.063 ± 0.007

*: Significantly different (p ≤ 0.05) from the chamber control group by Dunnett’s test.
: Data are presented as mean ± standard error. Days 1, 5, 12, and 16 were after the daily exposure, days 8 and 15 were before the daily exposure, and day 37 was after 21 days of recovery.

Table B-15Lung Deposition and Clearance Parameter Estimates for Male F344/NTac Rats in the Two-week Inhalation Study of Specular Hematite

Parameter	3 mg/m³	15 mg/m³	30 mg/m³	60 mg/m³
k (days⁻¹)	0.015	0.023	0.014	0.016
t_1/2 (days)	48	30	50	44
α (μg specular hematite/total lung per day)	8	43	63	126
A_e (μg specular hematite/total lung)	559	1,868	4,557	8,057

: Data are presented as group mean values.
: k = first-order lung clearance rate constant; t_1/2 = clearance half-life; α = deposition rate; A_e = steady-state lung burden.

Table B-16Lung Weights and Lung Burdens for Male Sprague Dawley Rats in the 39-week Inhalation Study of Blasting Sand

	Chamber Control	15 mg/m³	30 mg/m³	60 mg/m³
n	5	5	5	5
Absolute Lung Wt. (g)
Week 1	0.93 ± 0.03	0.98 ± 0.03	0.99 ± 0.05	0.98 ± 0.02
Week 4	1.18 ± 0.04	1.27 ± 0.03	1.28 ± 0.04	1.30 ± 0.04
Week 8	1.34 ± 0.04	1.39 ± 0.04	1.39 ± 0.02	1.71 ± 0.05**
Week 16	1.40 ± 0.05	1.55 ± 0.05	1.66 ± 0.05**	1.97 ± 0.07**
Week 26	1.48 ± 0.02	1.67 ± 0.05	1.92 ± 0.04**	2.43 ± 0.15**
Week 39	1.63 ± 0.02	1.70 ± 0.04	1.96 ± 0.09*	2.73 ± 0.16**
μg Si/g Lung
Week 1	0.6 ± 0.0	126.2 ± 6.3**	237.4 ± 8.0**	393.2 ± 24.5**
Week 4	0.6 ± 0.0	338.1 ± 6.4**	697.9 ± 36.8**	1,209.6 ± 54.3**
Week 8	0.6 ± 0.0	660.7 ± 25.1**	1,182.3 ± 103.3**	2,208.1 ± 130.6**
Week 16	0.6 ± 0.0	938.6 ± 74.2**	2,093.6 ± 126.2**	3,803.2 ± 141.8**
Week 26	0.6 ± 0.0	1,415.2 ± 96.3**	3,023.4 ± 78.6**	5,039.9 ± 105.6**
Week 39	0.6 ± 0.0	1,978.5 ± 81.9**	3,773.5 ± 163.8**	5,753.7 ± 224.2**
μg Si/Total Lung
Week 1	0.6 ± 0.0	124.5 ± 8.6**	235.1 ± 13.0**	387.8 ± 30.1**
Week 4	0.7 ± 0.0	428.7 ± 14.0**	896.3 ± 55.2**	1,575.5 ± 77.5**
Week 8	0.8 ± 0.0	916.2 ± 46.2**	1,634.0 ± 132.2**	3,766.0 ± 261.9**
Week 16	0.8 ± 0.0	1,461.0 ± 144.2**	3,484.5 ± 276.7**	7,486.0 ± 339.5**
Week 26	0.9 ± 0.0	2,356.7 ± 155.6**	5,822.0 ± 247.5**	12,230.5 ± 809.5**
Week 39	1.0 ± 0.0	3,376.5 ± 201.4**	7,450.0 ± 663.3**	15,643.5 ± 894.5**
μg Blasting Sand/g Lung
Week 1	1.5 ± 0.0	320.3 ± 15.9**	602.5 ± 20.2**	998.0 ± 62.3**
Week 4	1.5 ± 0.0	858.0 ± 16.3**	1,771.2 ± 93.5**	3,069.9 ± 137.8**
Week 8	1.5 ± 0.0	1,676.8 ± 63.6**	3,000.9 ± 262.2**	5,604.4 ± 331.4**
Week 16	1.5 ± 0.0	2,382.1 ± 188.4**	5,313.7 ± 320.3**	9,652.9 ± 359.8**
Week 26	1.5 ± 0.0	3,591.8 ± 244.4**	7,673.6 ± 199.4**	12,791.7 ± 268.0**
Week 39	1.5 ± 0.0	5,021.7 ± 207.9**	9,577.4 ± 415.7**	14,603.2 ± 569.1**
μg Blasting Sand/Total Lung
Week 1	1.4 ± 0.0	316.1 ± 21.9**	596.8 ± 33.0**	984.1 ± 76.5**
Week 4	1.8 ± 0.1	1,087.9 ± 35.5**	2,274.9 ± 140.0**	3,998.7 ± 196.7**
Week 8	2.0 ± 0.1	2,325.4 ± 117.4**	4,147.1 ± 335.5**	9,558.4 ± 664.7**
Week 16	2.1 ± 0.1	3,708.0 ± 366.0**	8,843.9 ± 702.2**	19,000.0 ± 861.8**
Week 26	2.2 ± 0.0	5,981.5 ± 395.0**	14,776.6 ± 628.1**	31,041.9 ± 2,054.5**
Week 39	2.5 ± 0.0	8,569.8 ± 511.2**	18,908.6 ± 1,683.4**	39,704.3 ± 2,270.3**
μg Blasting Sand/Total Lung per mg Blasting Sand/m³
Week 1	NA	21.1 ± 1.5	19.9 ± 1.1	16.4 ± 1.3
Week 4	NA	72.5 ± 2.4	75.8 ± 4.7	66.6 ± 3.3
Week 8	NA	155.0 ± 7.8	138.2 ± 11.2	159.3 ± 11.1
Week 16	NA	247.2 ± 24.4	294.8 ± 23.4	316.7 ± 14.4
Week 26	NA	398.8 ± 26.3	492.6 ± 20.9	517.4 ± 34.2
Week 39	NA	571.3 ± 34.1	630.3 ± 56.1	661.7 ± 37.8

*: Significantly different (p ≤ 0.05) from the chamber control group by the Williams or Shirley tests.
**: p ≤ 0.01.
: Data are presented as mean ± standard error. For values reported as below the limit of quantification, the values shown are the constant of half the limit of quantification. Statistical tests were performed only on data that were not exposure concentration normalized.
: NA = not applicable.

Table B-17Bronchial Lymph Node Weights and Bronchial Lymph Node Burdens for Male Sprague Dawley Rats in the 39-week Inhalation Study of Blasting Sand

	Chamber Control		15 mg/m³	30 mg/m³	60 mg/m³
n	5		5	5	5
Absolute Bronchial Lymph Node Wt. (g)
Week 1		0.012 ± 0.002	0.016 ± 0.005	0.016 ± 0.003	0.025 ± 0.003*
Week 4		0.020 ± 0.002	0.025 ± 0.003	0.022 ± 0.001	0.037 ± 0.004**
Week 8		0.023 ± 0.002	0.022 ± 0.004	0.026 ± 0.007	0.043 ± 0.007*
Week 16		0.017 ± 0.002	0.029 ± 0.006	0.045 ± 0.006	0.101 ± 0.018**
Week 26		0.018 ± 0.002	0.039 ± 0.005	0.077 ± 0.018**	0.079 ± 0.008**
Week 39		0.015 ± 0.002	0.115 ± 0.013	0.089 ± 0.019	0.193 ± 0.063**
μg Si/g Bronchial Lymph Node
Week 1		0.6 ± 0.0	0.6 ± 0.0	20.4 ± 19.9	0.6 ± 0.0
Week 4		0.6 ± 0.0	0.6 ± 0.0	0.6 ± 0.0	156.9 ± 63.0**
Week 8		0.6 ± 0.0	250.0 ± 69.6*	1,648.7 ± 462.4**	4,023.1 ± 1,064.6**
Week 16		0.6 ± 0.0	4,328.7 ± 1,340.9*	12,851.2 ± 744.0**	12,355.6 ± 863.2**
Week 26		0.6 ± 0.0	10,247.9 ± 834.9**	14,973.8 ± 1,845.7**	17,755.9 ± 4,395.9**
Week 39		0.6 ± 0.0	12,679.7 ± 1,598.5**	21,846.3 ± 2,886.6**	24,475.2 ± 4,539.0**
μg Si/Total Bronchial Lymph Node
Week 1		0.0 ± 0.0	0.0 ± 0.0	0.4 ± 0.4	0.0 ± 0.0
Week 4		0.0 ± 0.0	0.0 ± 0.0	0.0 ± 0.0	6.4 ± 2.7*
Week 8		0.0 ± 0.0	5.3 ± 1.9**	51.2 ± 22.0**	187.9 ± 58.0**
Week 16		0.0 ± 0.0	157.3 ± 55.8	580.0 ± 85.3**	1,245.9 ± 252.3**
Week 26		0.0 ± 0.0	401.3 ± 54.2**	1,022.3 ± 84.7**	1,481.4 ± 516.0**
Week 39		0.0 ± 0.0	1,460.7 ± 236.8**	1,767.6 ± 219.1**	3,773.6 ± 709.4**
μg Blasting Sand/g Bronchial Lymph Node
Week 1		1.4 ± 0.0	1.4 ± 0.0	51.9 ± 50.5	1.4 ± 0.0
Week 4		1.4 ± 0.0	1.4 ± 0.0	1.4 ± 0.0	398.1 ± 159.9**
Week 8		1.4 ± 0.0	634.5 ± 176.7*	4,184.4 ± 1,173.5**	10,210.9 ± 2,702.0**
Week 16		1.4 ± 0.0	10,986.6 ± 3,403.4*	32,617.2 ± 1,888.4**	31,359.3 ± 2,190.9**
Week 26		1.4 ± 0.0	26,009.9 ± 2,119.1**	38,004.5 ± 4,684.4**	45,065.9 ± 11,157.2**
Week 39		1.4 ± 0.0	32,181.9 ± 4,057.1**	55,447.4 ± 7,326.4**	62,119.8 ± 11,520.4**
μg Blasting Sand/Total Bronchial Lymph Node
Week 1		0.0 ± 0.0	0.0 ± 0.0	1.1 ± 1.1	0.0 ± 0.0
Week 4		0.0 ± 0.0	0.0 ± 0.0	0.0 ± 0.0	16.1 ± 6.8*
Week 8		0.0 ± 0.0	13.3 ± 4.9**	130.1 ± 55.8**	476.8 ± 147.1**
Week 16		0.0 ± 0.0	399.3 ± 141.6	1,472.0 ± 216.6**	3,162.1 ± 640.3**
Week 26		0.0 ± 0.0	1,018.5 ± 137.5**	2,594.5 ± 214.9**	3,759.8 ± 1,309.6**
Week 39		0.0 ± 0.0	3,707.4 ± 601.0**	4,486.3 ± 556.0**	9,577.7 ± 1,800.5**
μg Blasting Sand/Total Bronchial Lymph Node per mg Blasting Sand/m³
Week 1		NA	0.0 ± 0.0	0.0 ± 0.0	0.0 ± 0.0
Week 4		NA	0.0 ± 0.0	0.0 ± 0.0	0.3 ± 0.1
Week 8		NA	0.9 ± 0.3	4.3 ± 1.9	7.9 ± 2.5
Week 16		NA	26.6 ± 9.4	49.1 ± 7.2	52.7 ± 10.7
Week 26		NA	67.9 ± 9.2	86.5 ± 7.2	62.7 ± 21.8
Week 39		NA	247.2 ± 40.1	149.5 ± 18.5	159.6 ± 30.0

*: Significantly different (p ≤ 0.05) from the chamber control group by the Dunnett, Williams, Shirley, or Dunn tests.
**: p ≤ 0.01.
: Data are presented as mean ± standard error. For values reported as below the limit of quantification, the values shown are the constant of half the limit of quantification. Statistical tests were performed only on data that were not exposure concentration normalized.
: NA = not applicable.

Table B-18Mediastinal Lymph Node Weights and Mediastinal Lymph Node Burdens for Male Sprague Dawley Rats in the 39-week Inhalation Study of Blasting Sand

	Chamber Control		15 mg/m³	30 mg/m³	60 mg/m³
n	5		5	5	5
Absolute Mediastinal Lymph Node Wt. (g)
Week 1		0.027 ± 0.003	0.034 ± 0.005	0.032 ± 0.005	0.032 ± 0.005
Week 4		0.024 ± 0.004	0.032 ± 0.007	0.035 ± 0.005	0.033 ± 0.010
Week 8		0.032 ± 0.006	0.040 ± 0.007	0.043 ± 0.008	0.053 ± 0.008
Week 16		0.024 ± 0.004	0.031 ± 0.003	0.038 ± 0.007	0.046 ± 0.006*
Week 26		0.030 ± 0.005	0.052 ± 0.007	0.075 ± 0.009	0.101 ± 0.037*
Week 39		0.020 ± 0.001	0.034 ± 0.013	0.062 ± 0.017	0.072 ± 0.017*
μg Si/g Mediastinal Lymph Node
Week 1		10.4 ± 9.9	0.6 ± 0.0	0.6 ± 0.0	0.6 ± 0.0
Week 4		7.8 ± 7.2	0.6 ± 0.0	0.6 ± 0.0	114.3 ± 72.8
Week 8		0.6 ± 0.0	130.7 ± 71.6	1,317.6 ± 616.8**	2,728.4 ± 901.2**
Week 16		59.8 ± 31.7	2,200.3 ± 834.3	4,117.0 ± 1,746.9*	4,445.8 ± 1,964.6*
Week 26		0.6 ± 0.0	9,272.0 ± 1,665.8**	11,802.4 ± 1,061.5**	12,320.0 ± 1,721.2**
Week 39		13.2 ± 12.7	1,573.9 ± 1,124.5	14,494.7 ± 4,769.8*	20,352.0 ± 6,432.3**
μg Si/total Mediastinal Lymph Node
Week 1		0.3 ± 0.3	0.0 ± 0.0	0.0 ± 0.0	0.0 ± 0.0
Week 4		0.3 ± 0.3	0.0 ± 0.0	0.0 ± 0.0	4.9 ± 3.2
Week 8		0.0 ± 0.0	4.1 ± 1.8*	54.8 ± 19.5*	171.0 ± 79.1**
Week 16		1.4 ± 0.6	73.1 ± 27.3	170.8 ± 91.2*	218.7 ± 121.0**
Week 26		0.0 ± 0.0	450.6 ± 72.0**	888.4 ± 139.1**	1,266.2 ± 461.2**
Week 39		0.2 ± 0.2	105.8 ± 96.4	1,182.6 ± 456.9	1,767.0 ± 712.2**
μg Blasting Sand/g Mediastinal Lymph Node
Week 1		26.5 ± 25.1	1.4 ± 0.0	1.4 ± 0.0	1.4 ± 0.0
Week 4		19.8 ± 18.4	1.4 ± 0.0	1.4 ± 0.0	290.2 ± 184.8
Week 8		1.4 ± 0.0	331.8 ± 181.7	3,344.2 ± 1,565.4**	6,924.8 ± 2,287.3**
Week 16		151.9 ± 80.5	5,584.4 ± 2,117.5	10,449.4 ± 4,433.7*	11,283.8 ± 4,986.4*
Week 26		1.4 ± 0.0	23,532.9 ± 4,227.8**	29,955.5 ± 2,694.2**	31,268.9 ± 4,368.6**
Week 39		33.6 ± 32.2	3,994.6 ± 2,854.1	36,788.6 ± 12,106.2*	51,654.8 ± 6,325.6**
μg Blasting Sand/Total Mediastinal Lymph Node
Week 1		0.8 ± 0.7	0.0 ± 0.0	0.0 ± 0.0	0.0 ± 0.0
Week 4		0.7 ± 0.7	0.0 ± 0.0	0.0 ± 0.0	12.4 ± 8.1
Week 8		0.0 ± 0.0	10.5 ± 4.6*	139.1 ± 49.6*	434.0 ± 200.7**
Week 16		3.5 ± 1.6	185.5 ± 69.4	433.6 ± 231.5*	555.2 ± 307.0**
Week 26		0.0 ± 0.0	1,143.7 ± 182.7**	2,254.7 ± 352.9**	3,213.7 ± 1,170.5**
Week 39		0.6 ± 0.6	268.6 ± 244.7	3,001.6 ± 1,159.7	4,484.8 ± 1,807.7**
μg Blasting Sand/Total Mediastinal Lymph Node per mg Blasting Sand/m³
Week 1		NA	0.0 ± 0.0	0.0 ± 0.0	0.0 ± 0.0
Week 4		NA	0.0 ± 0.0	0.0 ± 0.0	0.2 ± 0.1
Week 8		NA	0.7 ± 0.3	4.6 ± 1.7	7.2 ± 3.3
Week 16		NA	12.4 ± 4.6	14.5 ± 7.7	9.3 ± 5.1
Week 26		NA	76.2 ± 12.2	75.2 ± 11.8	53.6 ± 19.5
Week 39		NA	17.9 ± 16.3	100.1 ± 38.7	74.7 ± 30.1

*: Significantly different (p ≤ 0.05) from the chamber control group by the Williams or Shirley tests.
**: p ≤ 0.01.
: Data are presented as mean ± standard error. For values reported as below the limit of quantification, the values shown are the constant of half the limit of quantification. Statistical tests were performed only on data that were not exposure concentration normalized.
: NA = not applicable.

Table B-19Lung Deposition and Clearance Parameter Estimates for Male Sprague Dawley Rats in the 39-week Inhalation Study of Blasting Sand

Parameter	15 mg/m³	30 mg/m³	60 mg/m³
k (days⁻¹)	0.003352 ± 0.000761	0.002556 ± 0.000841	0.000817 ± 0.000595
t_1/2 (days)	207 ± 47	271 ± 89	848 ± 618
D (μg blasting sand/total lung per day)	45.67 ± 1.80	98.04 ± 5.14	171.98 ± 7.17
L_ss (μg blasting sand/total lung)	13,624 ± 2,737	38,358 ± 11,090	210,387 ± 146,564

: Data are presented as mean ± standard error.
: k = first-order lung clearance rate constant; t_1/2 = clearance half-life; D = deposition rate; L_ss = steady-state lung burden.

Table B-20Lung Burden Overload Parameter Estimates for Male Sprague Dawley Rats in the 39-week Inhalation Study of Blasting Sand

Parameter	15 mg/m³	30 mg/m³	60 mg/m³
t* = time of onset of overload condition [(R(t)>1.0] (days)	137	55	30
L(t) = lung burden at t (mg blasting sand/lung)	5.0	5.0	5.1
R_max = maximum R(t) at 271 days (unitless)	1.6	3.8	8.4
Lung burden at R_max = L(t) at 271 days (mg blasting sand/lung)	8.1	19.2	41.8
Total dose = deposited blasting sand at 271 days (mg/lung)	12.4	26.6	46.6
Total blasting sand cleared = cleared blasting sand up through 271 days (mg/lung)	4.2	^7.4	^4.8
% Total blasting sand cleared = (total blasting sand cleared/total dose) × 100 (unitless)	34	28	10

: R(t) = ratio of the volume of retained blasting sand lung burden at time t and the threshold volume required for the onset of lung overload.

Table B-21Lung Weights and Lung Burdens for Male Sprague Dawley Rats in the 39-week Inhalation Study of Specular Hematite

	Chamber Control	15 mg/m³	30 mg/m³	60 mg/m³
n	5	5	5	5
Absolute Lung Wt. (g)
Week 1	0.93 ± 0.02	0.87 ± 0.01	0.91 ± 0.03	0.87 ± 0.03
Week 4	1.15 ± 0.03	1.16 ± 0.03	1.18 ± 0.04	1.17 ± 0.03
Week 8	1.30 ± 0.05	1.35 ± 0.06	1.36 ± 0.06	1.40 ± 0.03
Week 16	1.31 ± 0.04	1.44 ± 0.03*	1.55 ± 0.04**	1.56 ± 0.04**
Week 26	1.48 ± 0.04	1.52 ± 0.05	1.67 ± 0.04*	1.96 ± 0.05**
Week 39	1.51 ± 0.07^a	1.62 ± 0.03	1.76 ± 0.05**	2.11 ± 0.05**^a
μg Fe/g Lung
Week 1	49.16 ± 1.85	298.59 ± 20.00**	519.56 ± 29.77**	954.22 ± 35.07**
Week 4	63.41 ± 4.17	743.12 ± 25.15**	1,342.6 ± 71.31**	2,364.6 ± 104.08**
Week 8	70.11 ± 1.13	1,175.6 ± 102.53**	2,044.0 ± 111.09**	4,422.7 ± 113.60**
Week 16	82.04 ± 3.51	1,927.5 ± 197.10**	3,915.1 ± 312.96**	8,494.7 ± 383.33**
Week 26	85.84 ± 2.52	2,559.3 ± 315.11**	5,338.8 ± 382.59**	11,344 ± 467.86**
Week 39	95.50 ± 5.94^a	3,501.4 ± 154.31*	8,524.5 ± 567.31**	16,136 ± 1,023.4**^a
μg Fe/g Lung (Control Corrected)
Week 1	NA	249.428 ± 20.002	470.403 ± 29.771	905.059 ± 35.074
Week 4	NA	679.703 ± 25.154	1,279.13 ± 71.305	2,301.21 ± 104.078
Week 8	NA	1,105.53 ± 102.530	1,973.86 ± 111.092	4,352.62 ± 113.600
Week 16	NA	1,845.49 ± 197.093	3,833.07 ± 312.958	8,412.68 ± 383.334
Week 26	NA	2,473.47 ± 315.108	5,252.99 ± 382.587	11,257.7 ± 467.856
Week 39	NA	3,405.85 ± 154.306	8,429.03 ± 567.310	16,040.4 ± 1,023.37^a
μg Fe/Total Lung (Control Corrected)
Week 1	NA	217.575 ± 18.963	427.885 ± 25.625	791.542 ± 48.353
Week 4	NA	790.089 ± 36.127	1,502.32 ± 72.776	2,686.73 ± 93.504
Week 8	NA	1,495.88 ± 183.505	2,702.75 ± 249.133	6,114.12 ± 238.881
Week 16	NA	2,663.99 ± 319.488	5,926.81 ± 462.104	13,162.7 ± 732.920
Week 26	NA	3,825.04 ± 581.773	8,811.78 ± 827.017	22,038.5 ± 1,110.46
Week 39	NA	5,521.67 ± 269.869	14,968.5 ± 1,412.83	33,923.6 ± 2,696.84^a
μg Specular Hematite/g Lung (Control Corrected)
Week 1	NA	359.407 ± 28.822	677.814 ± 42.898	1,304.12 ± 50.539
Week 4	NA	979.400 ± 36.244	1,843.13 ± 102.746	3,315.86 ± 149.968
Week 8	NA	1,592.98 ± 147.737	2,844.17 ± 160.075	6,271.78 ± 163.688
Week 16	NA	2,659.20 ± 283.996	5,523.16 ± 450.948	12,122.0 ± 552.355
Week 26	NA	3,564.07 ± 454.045	7,569.15 ± 551.278	16,221.5 ± 674.145
Week 39	NA	4,907.56 ± 222.344	12,145.6 ± 817.449	23,113.0 ± 1,474.60^a
μg Specular Hematite/Total Lung (Control Corrected)
Week 1	NA	313.509 ± 27.324	616.549 ± 36.924	1,140.55 ± 69.673
Week 4	NA	1,138.46 ± 52.056	2,164.73 ± 104.865	3,871.37 ± 134.732
Week 8	NA	2,155.44 ± 264.416	3,894.45 ± 358.981	8,809.97 ± 344.208
Week 16	NA	3,838.61 ± 460.357	8,540.07 ± 665.855	18,966.5 ± 1,056.08
Week 26	NA	5,511.59 ± 838.290	12,697.1 ± 1,191.67	31,755.7 ± 1,600.09
Week 39	NA	7,956.30 ± 388.860	21,568.5 ± 2,035.77	48,881.2 ± 3,885.94^a
μg Specular Hematite/Total Lung per mg Specular Hematite/m³ (Control Corrected)
Week 1	NA	20.901 ± 1.822	20.552 ± 1.231	19.009 ± 1.161
Week 4	NA	75.897 ± 3.470	72.158 ± 3.495	64.523 ± 2.246
Week 8	NA	143.696 ± 17.628	129.815 ± 11.966	146.833 ± 5.737
Week 16	NA	255.907 ± 30.690	284.669 ± 22.195	316.108 ± 17.601
Week 26	NA	367.439 ± 55.886	423.236 ± 39.722	529.262 ± 26.668
Week 39	NA	530.420 ± 25.924	718.950 ± 67.859	814.687 ± 64.766^a

*: Significantly different (p ≤ 0.05) from the chamber control group by the Williams or Shirley tests.
**: p ≤ 0.01.
: Data are presented as mean ± standard error. Statistical tests were performed only on data that were not control corrected.
: NA = not applicable.
^a: n = 4.

Table B-22Bronchial Lymph Node Weights and Bronchial Lymph Node Burdens for Male Sprague Dawley Rats in the 39-week Inhalation Study of Specular Hematite

	Chamber Control		15 mg/m³	30 mg/m³	60 mg/m³
n	5		5	5	5
Absolute Bronchial Lymph Node Wt. (g)
Week 1		0.010 ± 0.002	0.011 ± 0.003	0.016 ± 0.003	0.011 ± 0.002
Week 4		0.026 ± 0.005	0.010 ± 0.003	0.020 ± 0.006	0.021 ± 0.004
Week 8		0.019 ± 0.003	0.020 ± 0.003	0.031 ± 0.004	0.028 ± 0.006
Week 16		0.014 ± 0.003	0.015 ± 0.003	0.027 ± 0.004	0.036 ± 0.007**
Week 26		0.013 ± 0.002	0.023 ± 0.005	0.040 ± 0.004**	0.050 ± 0.006**
Week 39		0.017 ± 0.006^a	0.025 ± 0.005	0.041 ± 0.005	0.051 ± 0.014*^a
μg Fe/Total Bronchial Lymph Node
Week 1		0.245 ± 0.245	0.322 ± 0.171	0.405 ± 0.162	0.198 ± 0.112
Week 4		0.943 ± 0.173	0.206 ± 0.206	1.255 ± 0.641	2.542 ± 0.641
Week 8		0.954 ± 0.165	1.272 ± 0.417	17.879 ± 4.765**	131.660 ± 35.090**
Week 16		1.498 ± 0.320	46.721 ± 18.599**	274.478 ± 118.208**	737.400 ± 103.996**
Week 26		1.713 ± 0.320	209.339 ± 112.024**	1,532.45 ± 341.267**	2,273.60 ± 397.628**
Week 39		3.360 ± 1.198^a	417.725 ± 102.586*	2,227.05 ± 359.973**	2,819.81 ± 1,232.548**^a
μg Fe/Total Bronchial Lymph Node (Control Corrected)
Week 1		NA	0.003 ± 0.001	0.146 ± 0.141	0.003 ± 0.001
Week 4		NA	0.003 ± 0.001	0.541 ± 0.536	1.610 ± 0.634
Week 8		NA	0.471 ± 0.305	16.925 ± 4.765	130.706 ± 35.090
Week 16		NA	45.223 ± 18.599	272.980 ± 118.208	735.902 ± 103.996
Week 26		NA	207.627 ± 112.024	1,530.74 ± 341.267	2,271.89 ± 397.628
Week 39		NA	414.365 ± 102.586	2,223.69 ± 359.973	2,816.45 ± 1,232.54^a
μg Fe/g Bronchial Lymph Node (Control Corrected)
Week 1		NA	0.305 ± 0.000	7.109 ± 6.804	0.305 ± 0.000
Week 4		NA	0.305 ± 0.000	13.736 ± 13.431	66.952 ± 23.086
Week 8		NA	19.536 ± 12.140	512.937 ± 126.805	4,632.85 ± 1,399.06
Week 16		NA	3,069.96 ± 1,345.72	9,608.73 ± 3,610.05	24,942.6 ± 5,803.36
Week 26		NA	6,613.07 ± 2,849.64	3,7020.1 ± 6,164.50	44,022.6 ± 3,908.51
Week 39		NA	19,295.5 ± 5,805.73	54,700.0 ± 6,555.39	48,099.2 ± 10,754.6^a
μg Specular hematite/g bronchial lymph node (Control Corrected)
Week 1		NA	0.440 ± 0.000	10.244 ± 9.804	0.440 ± 0.000
Week 4		NA	0.440 ± 0.000	19.794 ± 19.354	96.473 ± 33.266
Week 8		NA	28.151 ± 17.492	739.103 ± 182.716	6,675.57 ± 2,015.94
Week 16		NA	4,423.58 ± 1,939.07	13,845.4 ± 5,201.81	35,940.3 ± 8,362.19
Week 26		NA	9,528.92 ± 4,106.11	53,343.1 ± 8,882.56	63,433.2 ± 5,631.86
Week 39		NA	27,803.3 ± 8,365.61	78,818.4 ± 9,445.80	69,307.2 ± 15,496.6^a
μg Specular Hematite/Total Bronchial Lymph Node (Control Corrected)
Week 1		NA	0.005 ± 0.001	0.210 ± 0.203	0.005 ± 0.001
Week 4		NA	0.004 ± 0.002	0.779 ± 0.772	2.320 ± 0.913
Week 8		NA	0.679 ± 0.439	24.387 ± 6.867	188.337 ± 50.562
Week 16		NA	65.163 ± 26.800	393.343 ± 170.329	1,060.38 ± 149.850
Week 26		NA	299.174 ± 161.418	2,205.67 ± 491.739	3,273.61 ± 572.951
Week 39		NA	597.068 ± 147.818	3,204.16 ± 518.694	4,058.29 ± 1,775.99^a
μg Specular hematite/total bronchial lymph node per mg specular hematite/m³ (Control Corrected)
Week 1		NA	0.000 ± 0.000	0.007 ± 0.007	0.000 ± 0.000
Week 4		NA	0.000 ± 0.000	0.026 ± 0.026	0.039 ± 0.015
Week 8		NA	0.045 ± 0.029	0.813 ± 0.229	3.139 ± 0.843
Week 16		NA	4.344 ± 1.787	13.111 ± 5.678	17.673 ± 2.498
Week 26		NA	19.945 ± 10.761	73.522 ± 16.391	54.560 ± 9.549
Week 39		NA	39.805 ± 9.855	106.805 ± 17.290	67.638 ± 29.600^a

*: Significantly different (p ≤ 0.05) from the chamber control group by the Williams or Shirley tests.
**: p ≤ 0.01.
: Data are presented as mean ± standard error. Statistical tests were performed only on data that were not control corrected. For values reported as below the limit of quantification, the values shown are the constant of half the limit of quantification.
: NA = not applicable.
^a: n = 4.

Table B-23Mediastinal Lymph Node Weights and Mediastinal Lymph Node Burdens for Male Sprague Dawley Rats in the 39-week Inhalation Study of Specular Hematite

	Chamber Control	15 mg/m³	30 mg/m³	60 mg/m³
n	5	5	5	5
Absolute Mediastinal Lymph Node Wt. (g)
Week 1	0.018 ± 0.005	0.021 ± 0.003	0.026 ± 0.003	0.019 ± 0.001
Week 4	0.025 ± 0.003	0.024 ± 0.005	0.027 ± 0.005	0.023 ± 0.003
Week 8	0.025 ± 0.004	0.025 ± 0.002	0.026 ± 0.005	0.035 ± 0.008
Week 16	0.019 ± 0.002	0.020 ± 0.003	0.029 ± 0.004	0.034 ± 0.005*
Week 26	0.019 ± 0.004	0.032 ± 0.007	0.030 ± 0.002	0.046 ± 0.002**
Week 39	0.033 ± 0.009^a	0.031 ± 0.011	0.031 ± 0.006	0.060 ± 0.011^a
μg Fe/Total Mediastinal Lymph Node
Week 1	0.473 ± 0.473	0.893 ± 0.865	0.000 ± 0.000	0.128 ± 0.128
Week 4	0.194 ± 0.194	0.489 ± 0.489	0.139 ± 0.087	1.181 ± 0.490
Week 8	0.305 ± 0.222	0.041 ± 0.041	5.433 ± 3.848	193.108 ± 61.060**
Week 16	0.293 ± 0.265	41.371 ± 36.088	218.454 ± 75.099**	925.510 ± 368.088**
Week 26	10.06 ± 9.11	155.20 ± 88.09	270.45 ± 145.34*	952.30 ± 239.99**
Week 39	17.35 ± 9.88^a	277.40 ± 119.71*	554.53 ± 205.17**	2,836.7 ± 873.64**^a
μg Fe/Total Mediastinal Lymph Node (Control Corrected)
Week 1	NA	0.176 ± 0.028	0.219 ± 0.023	0.162 ± 0.008
Week 4	NA	0.207 ± 0.040	0.227 ± 0.046	0.192 ± 0.025
Week 8	NA	0.208 ± 0.021	4.186 ± 4.000	190.247 ± 62.967
Week 16	NA	41.337 ± 36.014	218.161 ± 75.099	925.040 ± 368.199
Week 26	NA	148.829 ± 86.492	260.829 ± 145.148	942.243 ± 239.989
Week 39	NA	260.049 ± 119.710	537.184 ± 205.170	2,819.34 ± 873.636^a
μg Fe/g Mediastinal Lymph Node (Control Corrected)
Week 1	NA	8.500 ± 0.000	8.500 ± 0.000	8.500 ± 0.000
Week 4	NA	8.500 ± 0.000	8.500 ± 0.000	8.500 ± 0.000
Week 8	NA	8.500 ± 0.000	106.23 ± 97.736	5,156.3 ± 1,494.29
Week 16	NA	1,392.47 ± 1,150.63	6,673.66 ± 1,634.18	25,051.1 ± 11,041.0
Week 26	NA	5,032.76 ± 3,039.27	9,028.06 ± 5,037.73	20,818.0 ± 5,546.83
Week 39	NA	10,365.0 ± 4,741.15	15,503.4 ± 4,040.53	46,919.3 ± 14,649.1^a
μg Specular Hematite/g Mediastinal Lymph Node (Control Corrected)
Week 1	NA	12.250 ± 0.000	12.250 ± 0.000	12.250 ± 0.000
Week 4	NA	12.250 ± 0.000	12.250 ± 0.000	12.250 ± 0.000
Week 8	NA	12.250 ± 0.000	153.079 ± 140.829	7,429.96 ± 2,153.16
Week 16	NA	2,006.44 ± 1,657.97	9,616.22 ± 2,354.72	36,096.7 ± 15,909.2
Week 26	NA	7,251.82 ± 4,379.35	13,008.7 ± 7,258.98	29,997.1 ± 7,992.56
Week 39	NA	14,935.1 ± 6,831.62	22,339.2 ± 5,822.09	67,607.0 ± 21,108.3^a
μg Specular Hematite/Total Mediastinal Lymph Node (Control Corrected)
Week 1	NA	0.254 ± 0.040	0.316 ± 0.033	0.234 ± 0.011
Week 4	NA	0.298 ± 0.058	0.327 ± 0.067	0.276 ± 0.036
Week 8	NA	0.300 ± 0.030	6.032 ± 5.764	274.131 ± 90.730
Week 16	NA	59.564 ± 51.893	314.352 ± 108.212	1,332.91 ± 530.546
Week 26	NA	214.451 ± 124.628	375.834 ± 209.147	1,357.70 ± 345.805
Week 39	NA	374.711 ± 172.493	774.041 ± 295.633	4,062.45 ± 1,258.84^a
μg Specular Hematite/Total Mediastinal Lymph node per mg Specular Hematite/m³ (Control Corrected)
Week 1	NA	0.017 ± 0.003	0.011 ± 0.001	0.004 ± 0.000
Week 4	NA	0.020 ± 0.004	0.011 ± 0.002	0.005 ± 0.001
Week 8	NA	0.020 ± 0.002	0.201 ± 0.192	4.569 ± 1.512
Week 16	NA	3.971 ± 3.460	10.478 ± 3.607	22.215 ± 8.842
Week 26	NA	14.297 ± 8.309	12.528 ± 6.972	22.628 ± 5.763
Week 39	NA	24.981 ± 11.500	25.801 ± 9.854	67.708 ± 20.981^a

*: Significantly different (p ≤ 0.05) from the chamber control group by the Dunnett, Williams, or Shirley tests.
**: p ≤ 0.01.
: Data are presented as mean ± standard error. Statistical tests were performed only on data that were not control corrected. For values reported as below the limit of quantification, the values shown are the constant of half the limit of quantification.
: NA = not applicable.
^a: n = 4.

Table B-24Lung Deposition and Clearance Parameter Estimates for Male Sprague Dawley Rats in the 39-week Inhalation Study of Specular Hematite

Parameter	15 mg/m³	30 mg/m³	60 mg/m³
k (days⁻¹)	0.00327 ± 0.00092	−0.00004 ± 0.00086	−0.00095 ± 0.00052
t_1/2 (days)	212 ± 59	–^a	–
D (μg specular hematite/total lung per day)	43.52 ± 3.79	76.34 ± 6.48	159.9 ± 8.1
L_ss (μg specular hematite/total lung)	13,325 ± 2,705	–	–

: Data are presented as mean ± standard error.
: k = first-order lung clearance rate constant; t_1/2 = clearance half-life; D = deposition rate; L_ss = steady-state lung burden.
^a: Resulting estimates are negative and so are not presented.

Table B-25Lung Burden Overload Parameter Estimates for Male Sprague Dawley Rats in the 39-week Inhalation Study of Specular Hematite

Parameter	15 mg/m³	30 mg/m³	60 mg/m³
t* = time of onset of overload condition [(R(t)>1.0] (days)	344	118	55
L(t) = lung burden at t (mg specular hematite/lung)	9.0	9.0	9.0
R_max = maximum R(t) at 271 days (unitless)	0.9	2.3	5.5
Lung burden at R_max = L(t) at 271 days (mg specular hematite/lung)	7.8	20.8	49.4
Total dose = deposited specular hematite at 271 days (mg/lung)	11.8	20.7	43.3
Total specular hematite cleared = cleared specular hematite up through 271 days (mg/lung)	4.0	–	–
% Total specular hematite cleared = (total specular hematite cleared/total dose) × 100 (unitless)	34	–	–

: R(t) = ratio of the volume of retained specular hematite lung burden at time t and the threshold volume required for the onset of lung overload. Resulting estimates are negative and so are not presented.

This is a work of the US government and distributed under the terms of the Public Domain

Bookshelf ID: NBK560071

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