A review of mammalian in vivo genotoxicity of hexavalent chromium: implications for oral carcinogenicity risk assessment

Figures & data

Figure 1. Oral carcinogenicity of Cr(VI). (A) Incidence of diffuse epithelial hyperplasia (DEH) in the duodenum and the combined adenoma/carcinoma (A/C) incidence in the duodenum and jejunum of B6CF1 mice exposed to Cr(VI) in drinking water for 2 years. (B) Incidence of oral tumors (squamous cell carcinoma) in F344 rats exposed to Cr(VI) in drinking water for 2 years. The vertical dotted line in each plot represents the current MCL for total chromium (0.1 ppm). The lowest data points in each plot represent the control group assigned 0.003 ppm, the 95^th percentile Cr(VI) concentration in U.S. water sources (see text). The red arrows point to the 1E-6 risk concentration of 0.07 ppb (0.00007 ppm).

Table 1. Summary of in vivo mutation assays on Cr(VI).

Species/Strain/Sex	Route	Dose	Units	Test Article	Duration/ Frequency	Analysis Time^a	Tissue	n	Results
ORAL MUCOSA
									MF x 10^-6
									(mean ± sd)
Rat, Big Blue TgF344, M	dw	0	ppm	Cr(VI)	28 days	3 days	gingival/palate	5	49.8 ± 17.8
(Na2Cr2O7*2H2O)	dw	180	ppm	Cr(VI)	28 days	3 days	gingival/palate	5	57.8 ± 9.1
Thompson et al. (2015c)	dw	10	ppm	4NQO (pos con)	28 days	3 days	gingival/palate	5	1818 ± 362
	dw	0	ppm	Cr(VI)	28 days	3 days	gingival/buccal	5	39.1 ± 7.5
	dw	180	ppm	Cr(VI)	28 days	3 days	gingival/buccal	5	44.4 ± 25.4
	dw	10	ppm	4NQO (pos con)	28 days	3 days	gingival/buccal	5	688 ± 250
DUODENUM
									MF x 10^-6
									(mean ± sd)
Rat, Big Blue TgF344, M	dw	0	ppm	Cr(VI)	28 days	3 days	duodenum	5	23.2 ± 4.8
(Na2Cr2O7*2H2O)	dw	180	ppm	Cr(VI)	28 days	3 days	duodenum	5	22.7 ± 8.4
Thompson et al. (2017b)	po	20	mg/kg	ENU (pos con)	1, 2, 3, 12, 19, & 26	3 days	duodenum	5	557 ± 116
									MF x 10^-5
									(mean ± sd)
Mouse, gpt delta	dw	0	ppm	Cr(VI)	28 days	3 days	duodenum	4	0.58 ± 0.31
(Na2Cr2O7*2H2O)	dw	30	ppm	Cr(VI)	28 days	3 days	duodenum	5	0.96 ± 0.69
Aoki et al. (2019)	dw	90	ppm	Cr(VI)	28 days	3 days	duodenum	5	0.91 ± 0.45
									(mean ± sd)
	dw	0	g/L	KBrO3	28 days	3 days	duodenum	4	0.35 ± 0.19
	dw	2	g/L	KBrO3 (pos con)	28 days	3 days	duodenum	5	1.03 ± 0.53
									(mean ± sd)
	dw	0	ppm	Cr(VI)	90 days	3 days	duodenum	6	0.80 ± 0.27
	dw	3	ppm	Cr(VI)	90 days	3 days	duodenum	4	0.62 ± 0.26
	dw	10	ppm	Cr(VI)	90 days	3 days	duodenum	4	0.49 ± 0.19
	dw	30	ppm	Cr(VI)	90 days	3 days	duodenum	4	0.77 ± 0.28
									MF (geo mean)
Mouse, B6C3F1, F	dw	0	ppm	Cr(VI)	90 days	NA	duodenum	5	2.4 × 10^-3
(Na2Cr2O7*2H2O)	dw	0.1	ppm	Cr(VI)	90 days	NA	duodenum	5	7.1 × 10^-4
O'Brien et al. (2013)	dw	1.4	ppm	Cr(VI)	90 days	NA	duodenum	5	9.9 × 10^-4
	dw	5	ppm	Cr(VI)	90 days	NA	duodenum	5	1.8 × 10^-3
	dw	20	ppm	Cr(VI)	90 days	NA	duodenum	5	1.6 × 10^-4
	dw	60	ppm	Cr(VI)	90 days	NA	duodenum	5	4.7 × 10^-4
	dw	180	ppm	Cr(VI)	90 days	NA	duodenum	5	1.2 × 10^-3
OTHER TISSUES									brown spots
Mouse, C57BL/6J/BOM, F	ip	0	mg/kg	K2CrO4	GD 8, 9, 10	2, 3, 4, 5 PP	coat	181	1 (0.5%)
(K2CrO4)	ip	10	mg/kg	K2CrO4	GD 8, 9, 10	2, 3, 4, 5 PP	coat	120	5 (4.2%)
Knudsen (1980)	ip	20	mg/kg	K2CrO4	GD 8, 9, 10	2, 3, 4, 5 PP	coat	52	1 (1.9%)
	ip	2.5	mg/kg	cyclophosphamide	GD 8, 9, 10	2, 3, 4, 5 PP	coat	141	5 (3.6%)
									MF x 10^-6
									(mean)
Mouse, MutaMouse, M	ip	0	mg/kg	K2CrO4	2 days	7 days	bone marrow	3	28.8
(K2CrO4)	ip	40	mg/kg	K2CrO4	2 days	7 days	bone marrow	3	32.2
Itoh and Shimada (1997)	ip	100	mg/kg	ENU	2 days	7 days	bone marrow	2	1821
	ip	0	mg/kg	K2CrO4	2 days	7 days	liver	3	35.8
	ip	40	mg/kg	K2CrO4	2 days	7 days	liver	2	72.3
	ip	100	mg/kg	ENU	2 days	7 days	liver	2	205
									MF x 10^-6
									(mean)
Mouse, MutaMouse, M	ip	0	mg/kg	K2CrO4	1 day	1 day	bone marrow	5	46.4 ± 12.6
(K2CrO4)	ip	40	mg/kg	K2CrO4	1 day	1 day	bone marrow	5	76.8 ± 14.5
Itoh and Shimada (1998)	ip	40	mg/kg	K2CrO4	1 day	7 days	bone marrow	5	39.4 ± 11.0
	ip	0	mg/kg	K2CrO4	1 day	1 day	liver	5	51.5 ± 13.7
	ip	40	mg/kg	K2CrO4	1 day	1 day	liver	5	43.3 ± 12.4
	ip	40	mg/kg	K2CrO4	1 day	7 days	liver	5	104.8 ± 34.5
									MF x 10^-5
									(mean ± sd)
Mouse, Big Blue, F	it	0	mg/kg	saline	1 day	4 weeks	lung	4	2.6 ± 0.5
(K2Cr2O7)	it	1.7	mg/kg	K2Cr2O7	1 day	4 weeks	lung	4	4.1 ± 0.8
Cheng et al. (1998)	it	3.4	mg/kg	K2Cr2O7	1 day	4 weeks	lung	4	7.7 ± 2.2
	it	6.8	mg/kg	K2Cr2O7	1 day	4 weeks	lung	4	12.5 ± 1.7
									MF x 10^-5
Mouse, Big Blue, F	it	0	mg/kg	K2Cr2O7	1 day	1 weeks	lung	3	3.4
(K2Cr2O7)	it	6.8	mg/kg	K2Cr2O7	1 day	1 weeks	lung	3	4.6
Cheng et al. (2000)	it	6.8	mg/kg	K2Cr2O7	1 day	2 weeks	lung	3	8.8
	it	6.8	mg/kg	K2Cr2O7	1 day	4 weeks	lung	3	14.6
									MF x 10^-5
	it	0	mg/kg	K2Cr2O7	1 day	4 weeks	lung	4	2.6
	it	6.8	mg/kg	K2Cr2O7	1 day	4 weeks	lung	4	12.5
	it	0	mg/kg	K2Cr2O7	1 day	4 weeks	kidney	3	1.8
	it	6.8	mg/kg	K2Cr2O7	1 day	4 weeks	kidney	4	6.7
	it	0	mg/kg	K2Cr2O7	1 day	4 weeks	liver	3	2
	it	6.8	mg/kg	K2Cr2O7	1 day	4 weeks	liver	4	3.8
									MF x 10^-5
	it	0	mg/kg	BSO	1 day	4 weeks	lung	4	3.1
	it	6.8	mg/kg	K2Cr2O7 & BSO	1 day	4 weeks	lung	4	6.9
	it	0	mg/kg	GSH-ester	1 day	4 weeks	lung	2	3.3
	it	6.8	mg/kg	K2Cr2O7 & GSH-ester	1 day	4 weeks	lung	4	14.1
									spots/RPE
									(mean)
Mouse, C57BL/6Jp^un/p^un, F	dw	0	ppm	K2Cr2O7	10.5-20.5 DPC	20 days of age	eye spot	55	5.5
(K2Cr2O7, CrCl3)	dw	62.6	ppm	K2Cr2O7	10.5-20.5 DPC	20 days of age	eye spot	24	7.1
Kirpnick-Sobol et al. (2006)	dw	125	ppm	K2Cr2O7	10.5-20.5 DPC	20 days of age	eye spot	14	7.6

^aafter last exposure

BSO: buthionine sulphoximine; DPC: days postconception; dw: drinking water; ENU: N-ethyl-N-nitrosourea; F: female; geo: geometric; ip: intraperitoneal; it: intratracheal; iv: intravenous; M: male; MF: mutant frequency; mg/kg: milligrams per kilogram; n: number of animals; NA: not available; po: oral gavage; pos con: positive control; PP: postpartum week; ppm: parts per million; RPE: retinal pigment epithelium; sd: standard deviation.

Bolded values differ significantly from control.

Figure 2. Chromium dosimetry in the rodent duodenum. (A) Tissue Cr levels in mouse and rat duodenum following exposure to Cr(VI) for 90 days (note: rats were not exposed to 5 ppm Cr(VI)). (B) XRF images from an unstained transverse section of duodenum from a female B6C3F1 mouse exposed to 180 ppm Cr(VI) for 90 days. (Left) full transverse section with chromium (Cr) XRF. (Right) Magnification of the region in the yellow box, with XRF images for calcium (Ca), sulfur (S), and Cr. Signal for Ca and S are contiguous throughout the villus and crypt regions, whereas Cr signal is very high in the villi, but low or absent in the crypt. (C) Chromium XRF image of an unstained 5-µm transverse section from the duodenum of a female F344 rat exposed to 180 ppm Cr(VI) for 90 days. Adapted from Thompson et al. (2011, 2015).

Figure 3. Eye spot test (in vivo mutation) results from Kirpnick-Sobol et al. (2006). Data were extracted from Figure 4 in Kirpnick-Sobol et al. (2006) using WebPlotDigitizer v4.3 and replotted in Prism 9. **p-value < 0.01; ****p-value < 0.0001.

Table 2. Summary of in vivo chromosomal damage assays on Cr(VI).

Species/Strain/Sex	Route	Dose	units	Test Article	Duration/ Frequency	Analysis Time^a	Tissue	n	Measurement
DUODENUM									MN/enterocytes
Mouse, B6C3F1, F	dw	0	ppm	Cr(VI)	90 days	NA	10 crypts/animal	5	0/1921
(Na2Cr2O7*2H2O)	dw	0.1	ppm	Cr(VI)	90 days	NA	10 crypts/animal	5	0/1707
O’Brien et al. (2013)	dw	1.4	ppm	Cr(VI)	90 days	NA	10 crypts/animal	4	0/1825
	dw	5	ppm	Cr(VI)	90 days	NA	10 crypts/animal	5	0/1420
	dw	20	ppm	Cr(VI)	90 days	NA	10 crypts/animal	5	0/2386
	dw	60	ppm	Cr(VI)	90 days	NA	10 crypts/animal	5	0/2746
	dw	180	ppm	Cr(VI)	90 days	NA	10 crypts/animal	5	0/3194
								n	MN (KN) across 15 slides
Mouse, B6C3F1, F	dw	0	ppm	Cr(VI)	7 days	NA	villus region (3 slides)	5	1 (0)
(Na2Cr2O7*2H2O)	dw	0.1	ppm	Cr(VI)	7 days	NA	villus region (3 slides)	5	3 (0)
O’Brien et al. (2013)	dw	1.4	ppm	Cr(VI)	7 days	NA	villus region (3 slides)	5	5 (0)
	dw	5	ppm	Cr(VI)	7 days	NA	villus region (3 slides)	5	2 (0)
	dw	20	ppm	Cr(VI)	7 days	NA	villus region (3 slides)	5	1 (2)
	dw	60	ppm	Cr(VI)	7 days	NA	villus region (3 slides)	5	6 (3)
	dw	180	ppm	Cr(VI)	7 days	NA	villus region (3 slides)	5	11 (9)
	dw	0	ppm	Cr(VI)	90 days	NA	villus region (3 slides)	5	1 (0)
	dw	0.1	ppm	Cr(VI)	90 days	NA	villus region (3 slides)	5	1 (1)
	dw	1.4	ppm	Cr(VI)	90 days	NA	villus region (3 slides)	5	2 (0)
	dw	5	ppm	Cr(VI)	90 days	NA	villus region (3 slides)	4	0 (0)
	dw	20	ppm	Cr(VI)	90 days	NA	villus region (3 slides)	5	2 (5)
	dw	60	ppm	Cr(VI)	90 days	NA	villus region (3 slides)	5	9 (6)
	dw	180	ppm	Cr(VI)	90 days	NA	villus region (3 slides)	5	9 (25)
									MN (KN) across 15 slides
Mouse, B6C3F1, F	dw	0	ppm	Cr(VI)	7 days	NA	crypt region (3 slides)	5	1 (0)
(Na2Cr2O7*2H2O)	dw	0.1	ppm	Cr(VI)	7 days	NA	crypt region (3 slides)	5	0 (0)
EPL Report (2013)	dw	1.4	ppm	Cr(VI)	7 days	NA	crypt region (3 slides)	5	0 (0)
	dw	5	ppm	Cr(VI)	7 days	NA	crypt region (3 slides)	5	0 (0)
	dw	20	ppm	Cr(VI)	7 days	NA	crypt region (3 slides)	5	0 (0)
	dw	60	ppm	Cr(VI)	7 days	NA	crypt region (3 slides)	5	0 (0)
	dw	180	ppm	Cr(VI)	7 days	NA	crypt region (3 slides)	5	0 (1)
	dw	0	ppm	Cr(VI)	90 days	NA	crypt region (3 slides)	5	2 (0)
	dw	0.1	ppm	Cr(VI)	90 days	NA	crypt region (3 slides)	5	2 (1)
	dw	1.4	ppm	Cr(VI)	90 days	NA	crypt region (3 slides)	5	1 (0)
	dw	5	ppm	Cr(VI)	90 days	NA	crypt region (3 slides)	4	1 (0)
	dw	20	ppm	Cr(VI)	90 days	NA	crypt region (3 slides)	5	0 (1)
	dw	60	ppm	Cr(VI)	90 days	NA	crypt region (3 slides)	5	0 (1)
	dw	180	ppm	Cr(VI)	90 days	NA	crypt region (3 slides)	5	0 (0)
									MN/enterocytes
Mouse, B6C3F1, F	dw	0	ppm	Cr(VI)	7 days	24 h	≥15 crypts/animal	10	4/6694
(Na2Cr2O7*2H2O)	dw	1.4	ppm	Cr(VI)	7 days	24 h	≥15 crypts/animal	5	1/3159
Thompson et al. (2015b)	dw	21	ppm	Cr(VI)	7 days	24 h	≥15 crypts/animal	5	1/3946
	dw	180	ppm	Cr(VI)	7 days	24 h	≥15 crypts/animal	5	0/5161
	po	50	mg/kg	cyclophosphamide	7 days	24 h	≥15 crypts/animal	5	30/3447
OTHER TISSUES									%MN (mean)
Mouse, NMRI, U	ip	0	mg/kg	potassium chromate	2 days	6 h	bone marrow PCE	4	3.1
(potassium chromate)	ip	12.12	mg/kg	potassium chromate	2 days	6 h	bone marrow PCE	4	4.8
Wild (1978)	ip	24.25	mg/kg	potassium chromate	2 days	6 h	bone marrow PCE	4	9.6
	ip	48.5	mg/kg	potassium chromate	2 days	6 h	bone marrow PCE	4	15
									% abnormal (mean)
Rat, Wistar, U	ip	0	mg/kg	K2Cr2O7	2 days	24 h	lymphocytes	1900	4.4
(K2Cr2O7)	ip	12	mg/kg	K2Cr2O7	2 days	24 h	lymphocytes	200	5.5
Newton & Lilly (1986)	ip	18	mg/kg	K2Cr2O7	2 days	24 h	lymphocytes	500	6.2
	ip	21	mg/kg	K2Cr2O7	2 days	24 h	lymphocytes	400	8.2
	iv	24	mg/kg	K2Cr2O7	2 days	24 h	lymphocytes	300	4.3
	iv	30	mg/kg	K2Cr2O7	2 days	24 h	lymphocytes	300	4.7
	iv	36	mg/kg	K2Cr2O7	2 days	24 h	lymphocytes	300	7.7
	ip	35	mg/kg	1-phenyl-3, 3 dimethyltriazine	NS	NS	lymphocytes	200	14.5
	po	0.7	mg/kg.g	aflotoxin	NS	NS	lymphocytes	300	21
	ip	0	mg/kg	K2Cr2O7	1 day	NS	bone marrow	900	6.2
	ip	21	mg/kg	K2Cr2O7	1 day	24 h	bone marrow	200	13
	iv	12	mg/kg	K2Cr2O7	1 day	24 h	bone marrow	200	8.5
	iv	18	mg/kg	K2Cr2O7	1 day	24 h	bone marrow	200	16.5
	iv	24	mg/kg	K2Cr2O7	1 day	24 h	bone marrow	200	19
	iv	36	mg/kg	K2Cr2O7	1 day	24 h	bone marrow	200	35.5
									%MN (mean ± sd)
Mouse, Ms/Ae, M	ip	0	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.20 ± 0.12
(K2Cr2O7)	ip	10	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.23 ± 0.05
Shindo et al. (1989)	ip	20	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.78 ± 0.38
	ip	40	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	2.23 ± 0.92
	ip	80	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	2.10 ± 0.37
	po	0	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.33 ± 0.22
	po	20	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.43 ± 0.05
	po	40	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.38 ± 0.19
	po	80	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.18 ± 0.22
	po	160	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.35 ± 0.17
Mouse, CD-1, M	ip	0	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.08 ± 0.15
	ip	10	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.05 ± 0.06
	ip	20	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.18 ± 0.13
	ip	40	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.25 ± 0.06
	ip	80	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	1.18 ± 0.52
	po	0	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0
	po	20	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.28 ± 0.17
	po	40	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.15 ± 0.13
	po	80	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.25 ± 0.10
	po	160	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.18 ± 0.15
	po	320	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	6?	0.38 ± 0.25
									CA/cell (mean ± sd)
Mouse, Swiss Albino, M	po	0	mg/kg	CrO3	1 day	24 h	bone marrow	5	0.018 ± 0.011
(CrO3)	po	20	mg/kg	CrO3	1 day	24 h	bone marrow	5	0.08 ± 0.0071
Sarkar et al. (1993)
									%MN (mean ± se)
Mouse, Slc:ddY, M	ip	0	mg/kg	K2CrO4	2 days	24 h	bone marrow PCE	20	0.14 ± 0.05
(K2CrO4, CrCl3)	ip	30	mg/kg	K2CrO4	2 days	24 h	bone marrow PCE	5	0.46 ± 0.08
Itoh and Shimada (1996)	ip	40	mg/kg	K2CrO4	2 days	24 h	bone marrow PCE	5	0.54 ± 0.07
	ip	50	mg/kg	K2CrO4	2 days	24 h	bone marrow PCE	5	0.76 ± 0.19
	ip	62.5	mg/kg	Cr(III), CrCl3	2 days	24 h	bone marrow PCE	5	0.10 ± 0.03
	ip	125	mg/kg	Cr(III), CrCl3	2 days	24 h	bone marrow PCE	5	0.06 ± 0.02
	ip	250	mg/kg	Cr(III), CrCl3	2 days	24 h	bone marrow PCE	3	0.17 ± 0.09
	ip	0.5	mg/kg	Mitomycin C	2 days	24 h	bone marrow PCE	20	2.27 ± 0.15
									%MN (mean ± se)
Mouse, Swiss-Webster, M	dw	0	ppm	K2Cr2O7	2 days	NA	bone marrow PCE	5	0.18 ± 0.04
(K2Cr2O7)	dw	1	ppm	K2Cr2O7	2 days	NA	bone marrow PCE	5	0.16 ± 0.05
Mirsalis et al. (1996)	dw	5	ppm	K2Cr2O7	2 days	NA	bone marrow PCE	5	0.10 ± 0.04
	dw	20	ppm	K2Cr2O7	2 days	NA	bone marrow PCE	5	0.24 ± 0.04
Mouse, Swiss-Webster, F	dw	0	ppm	K2Cr2O7	2 days	NA	bone marrow PCE	5	0.18 ± 0.09
(K2Cr2O7)	dw	1	ppm	K2Cr2O7	2 days	NA	bone marrow PCE	5	0.24 ± 0.04
Mirsalis et al. (1996)	dw	5	ppm	K2Cr2O7	2 days	NA	bone marrow PCE	5	0.16 ± 0.05
	dw	20	ppm	K2Cr2O7	2 days	NA	bone marrow PCE	5	0.16 ± 0.02
									%MN (mean ± se)
Mouse, Swiss-Webster, M	po	0	ppm	K2Cr2O7	2 days	24 h	bone marrow PCE	5	0.26 ± 0.07
(K2Cr2O7)	po	1	ppm	K2Cr2O7	2 days	24 h	bone marrow PCE	5	0.16 ± 0.05
Mirsalis et al. (1996)	po	5	ppm	K2Cr2O7	2 days	24 h	bone marrow PCE	5	0.12 ± 0.04
	po	20	ppm	K2Cr2O7	2 days	24 h	bone marrow PCE	5	0.14 ± 0.07
	po	300	ppm	urethane	2 days	24 h	bone marrow PCE	5	2.21 ± 0.37
Mouse, Swiss-Webster, F	po	0	ppm	K2Cr2O7	2 days	24 h	bone marrow PCE	5	0.18 ± 0.05
(K2Cr2O7)	po	1	ppm	K2Cr2O7	2 days	24 h	bone marrow PCE	5	0.12 ± 0.05
Mirsalis et al. (1996)	po	5	ppm	K2Cr2O7	2 days	24 h	bone marrow PCE	5	0.14 ± 0.05
	po	20	ppm	K2Cr2O7	2 days	24 h	bone marrow PCE	5	0.14 ± 0.07
	po	300	ppm	urethane	2 days	24 h	bone marrow PCE	5	1.87 ± 0.24
									CA/cell (mean ± sd)
Mouse, Swiss-Webster, M	po	0	mg/kg	K2Cr2O7	1 day	24 h	bone marrow	5	0.016 ± 0.008
(K2Cr2O7)	po	20	mg/kg	K2Cr2O7	1 day	24 h	bone marrow	5	0.068 ± 0.0148
Mukherjee et al. (1997)
									%MN (mean ± se)
Mouse, Balb C, M	ip	0	mg/kg	K2Cr2O7	1 day	30 h	bone marrow PCE	6	0.22 ± 0.03
(K2Cr2O7)	ip	20.8	mg/kg	K2Cr2O7	1 day	30 h	bone marrow PCE	6	1.06 ± 0.11
Wronska-Nofer et al. (1999)	ip	2.5	mg/kg	Mitomycin C	1 day	30 h	bone marrow PCE	6	3.82 ± 0.54
									%MN (mean ± se)
Mouse, BDFI, M	dw	0	ppm	K2Cr2O7	0 days	NA	blood NCE	10	1.07 ± 0.073
(K2Cr2O7)	dw	10	ppm	K2Cr2O7	0 days	NA	blood NCE	10	1.10 ± 0.044
De Flora et al. (2006)	dw	20	ppm	K2Cr2O7	0 days	NA	blood NCE	10	0.98 ± 0.059
	dw	0	ppm	K2Cr2O7	5 days	NA	blood NCE	10	1.16 ± 0.064
	dw	10	ppm	K2Cr2O7	5 days	NA	blood NCE	10	1.10 ± 0.055
	dw	20	ppm	K2Cr2O7	5 days	NA	blood NCE	10	1.02 ± 0.032
	dw	0	ppm	K2Cr2O7	12 days	NA	blood NCE	10	1.05 ± 0.050
	dw	10	ppm	K2Cr2O7	12 days	NA	blood NCE	10	0.97 ± 0.045
	dw	20	ppm	K2Cr2O7	12 days	NA	blood NCE	10	1.05 ± 0.055
	dw	0	ppm	K2Cr2O7	20 days	NA	blood NCE	10	1.03 ± 0.078
	dw	10	ppm	K2Cr2O7	20 days	NA	blood NCE	10	0.95 ± 0.056
	dw	20	ppm	K2Cr2O7	20 days	NA	blood NCE	10	0.94 ± 0.068
									%MN (mean ± se)
Mouse, BDFI, M	dw	0		K2Cr2O7	20 days	NA	bone marrow PCE	10	1.29 ± 0.36
(K2Cr2O7)	dw	10	ppm	K2Cr2O7	20 days	NA	bone marrow PCE	10	0.80 ± 0.36
De Flora et al. (2006)	dw	20	ppm	K2Cr2O7	20 days	NA	bone marrow PCE	10	0.88 ± 0.30
	po	50	mg/kg	K2Cr2O7	1 day	24 h	bone marrow PCE	10	0.76 ± 0.24
	ip	50	mg/kg	K2Cr2O7	1 day	24 h (NES)	bone marrow PCE	10	9.34 ± 1.53
									%MN (mean ± se)
Mouse, BDFI, M	dw	0	ppm	Na2Cr2O7	0 days	NA	blood NCE	10	0.95 ± 0.028
(Na2Cr2O7, CrK(SO4)2)	dw	5	ppm	Na2Cr2O7	0 days	NA	blood NCE	10	0.96 ± 0.061
De Flora et al. (2006)	dw	50	ppm	Na2Cr2O7	0 days	NA	blood NCE	10	0.71 ± 0.075
	dw	500	ppm	Na2Cr2O7	0 days	NA	blood NCE	10	0.90 ± 0.102
	dw	500	ppm	Cr(III), CrK(SO4)2	0 days	NA	blood NCE	10	0.87 ± 0.058
	dw	0	ppm	Na2Cr2O7	14 days	NA	blood NCE	10	0.93 ± 0.039
	dw	5	ppm	Na2Cr2O7	14 days	NA	blood NCE	10	0.92 ± 0.082
	dw	50	ppm	Na2Cr2O7	14 days	NA	blood NCE	10	0.82 ± 0.059
	dw	500	ppm	Na2Cr2O7	14 days	NA	blood NCE	10	0.71 ± 0.096
	dw	500	ppm	Cr(III), CrK(SO4)2	14 days	NA	blood NCE	10	0.88 ± 0.064
	dw	0	ppm	Na2Cr2O7	28 days	NA	blood NCE	10	0.78 ± 0.105
	dw	5	ppm	Na2Cr2O7	28 days	NA	blood NCE	10	0.77 ± 0.13
	dw	50	ppm	Na2Cr2O7	28 days	NA	blood NCE	10	0.78 ± 0.076
	dw	500	ppm	Na2Cr2O7	28 days	NA	blood NCE	10	0.73 ± 0.067
	dw	500	ppm	Cr(III), CrK(SO4)2	28 days	NA	blood NCE	10	0.70 ± 0.081
	dw	0	ppm	Na2Cr2O7	56 days	NA	blood NCE	10	0.88 ± 0.035
	dw	5	ppm	Na2Cr2O7	56 days	NA	blood NCE	10	0.77 ± 0.087
	dw	50	ppm	Na2Cr2O7	56 days	NA	blood NCE	10	0.71 ± 0.072
	dw	500	ppm	Na2Cr2O7	56 days	NA	blood NCE	10	0.76 ± 0.092
	dw	500	ppm	Cr(III), CrK(SO4)2	56 days	NA	blood NCE	10	0.83 ± 0.075
	dw	0	ppm	Na2Cr2O7	147 days	NA	blood NCE	10	0.81 ± 0.067
	dw	5	ppm	Na2Cr2O7	147 days	NA	blood NCE	10	0.85 ± 0.091
	dw	50	ppm	Na2Cr2O7	147 days	NA	blood NCE	10	0.77 ± 0.062
	dw	500	ppm	Na2Cr2O7	147 days	NA	blood NCE	10	0.62 ± 0.075
	dw	500	ppm	Cr(III), CrK(SO4)2	147 days	NA	blood NCE	10	0.76 ± 0.084
	dw	0	ppm	Na2Cr2O7	210 days	NA	bone marrow PCE	10	1.83 ± 0.254
	dw	5	ppm	Na2Cr2O7	210 days	NA	bone marrow PCE	10	1.89 ± 0.621
	dw	50	ppm	Na2Cr2O7	210 days	NA	bone marrow PCE	10	1.94 ± 0.510
	dw	500	ppm	Na2Cr2O7	210 days	NA	bone marrow PCE	10	2.38 ± 0.616
	dw	500	ppm	Cr(III), CrK(SO4)2	210 days	NA	bone marrow PCE	10	1.43 ± 0.403
									%MN (mean ± se)
Mouse, BDFI, F	dw	0	ppm	Na2Cr2O7	0 days	NA	blood NCE	10	0.75 ± 0.050
(Na2Cr2O7, CrK(SO4)2)	dw	5	ppm	Na2Cr2O7	0 days	NA	blood NCE	10	0.82 ± 0.092
De Flora et al. (2006)	dw	50	ppm	Na2Cr2O7	0 days	NA	blood NCE	10	0.83 ± 0.076
	dw	500	ppm	Na2Cr2O7	0 days	NA	blood NCE	10	0.77 ± 0.096
	dw	500	ppm	Cr(III), CrK(SO4)2	0 days	NA	blood NCE	10	0.81 ± 0.064
	dw	0	ppm	Na2Cr2O7	14 days	NA	blood NCE	10	0.71 ± 0.051
	dw	5	ppm	Na2Cr2O7	14 days	NA	blood NCE	10	0.63 ± 0.036
	dw	50	ppm	Na2Cr2O7	14 days	NA	blood NCE	10	0.77 ± 0.092
	dw	500	ppm	Na2Cr2O7	14 days	NA	blood NCE	10	0.75 ± 0.028
	dw	500	ppm	Cr(III), CrK(SO4)2	14 days	NA	blood NCE	10	0.64 ± 0.052
	dw	0	ppm	Na2Cr2O7	28 days	NA	blood NCE	10	0.71 ± 0.040
	dw	5	ppm	Na2Cr2O7	28 days	NA	blood NCE	10	0.68 ± 0.043
	dw	50	ppm	Na2Cr2O7	28 days	NA	blood NCE	10	0.57 ± 0.072
	dw	500	ppm	Na2Cr2O7	28 days	NA	blood NCE	10	0.53 ± 0.067
	dw	500	ppm	Cr(III), CrK(SO4)2	28 days	NA	blood NCE	10	0.61 ± 0.058
	dw	0	ppm	Na2Cr2O7	56 days	NA	blood NCE	10	0.69 ± 0.083
	dw	5	ppm	Na2Cr2O7	56 days	NA	blood NCE	10	0.68 ± 0.047
	dw	50	ppm	Na2Cr2O7	56 days	NA	blood NCE	10	0.63 ± 0.054
	dw	500	ppm	Na2Cr2O7	56 days	NA	blood NCE	10	0.67 ± 0.064
	dw	500	ppm	Cr(III), CrK(SO4)2	56 days	NA	blood NCE	10	0.60 ± 0.085
	dw	0	ppm	Na2Cr2O7	147 days	NA	blood NCE	10	0.60 ± 0.053
	dw	5	ppm	Na2Cr2O7	147 days	NA	blood NCE	10	0.54 ± 0.059
	dw	50	ppm	Na2Cr2O7	147 days	NA	blood NCE	10	0.61 ± 0.057
	dw	500	ppm	Na2Cr2O7	147 days	NA	blood NCE	10	0.63 ± 0.061
	dw	500	ppm	Cr(III), CrK(SO4)2	147 days	NA	blood NCE	10	0.69 ± 0.072
	dw	0	ppm	Na2Cr2O7	210 days	NA	bone marrow PCE	10	1.44 ± 0.603
	dw	5	ppm	Na2Cr2O7	210 days	NA	bone marrow PCE	10	1.33 ± 0.878
	dw	50	ppm	Na2Cr2O7	210 days	NA	bone marrow PCE	10	1.42 ± 0.632
	dw	500	ppm	Na2Cr2O7	210 days	NA	bone marrow PCE	10	1.25 ± 0.254
	dw	500	ppm	Cr(III), CrK(SO4)2	210 days	NA	bone marrow PCE	10	1.22 ± 0.63
									%MN (mean ± se)
Mouse, Swiss Albino, Pregnant	dw	0	ppm	Na2Cr2O7	GD1-18	NA	bone marrow PCE	5	1.75 ± 0.500
(Na2Cr2O7, K2Cr2O7)	dw	5	ppm	Na2Cr2O7	GD1-18	NA	bone marrow PCE	5	1.13 ± 0.515
De Flora et al. (2006)	dw	10	ppm	Na2Cr2O7	GD1-18	NA	bone marrow PCE	5	2.19 ± 0.614
	dw	10	ppm	K2Cr2O7	GD1-18	NA	bone marrow PCE	5	1.56 ± 0.466
	ip	50	mg/kg	Na2Cr2O7	on GD17	24 h	bone marrow PCE	5	5.84 ± 0.893
	ip	50	mg/kg	K2Cr2O7	on GD17	24 h	bone marrow PCE	5	5.19 ± 0.724
									%MN (mean ± se)
Mouse, Swiss Albino Fetuses	dw	0	ppm	Na2Cr2O7	GD1-18	NA	fetal blood	5	3.60 ± 0.551
(Na2Cr2O7, K2Cr2O7)	dw	5	ppm	Na2Cr2O7	GD1-18	NA	fetal blood	5	4.03 ± 0.472
De Flora et al. (2006)	dw	10	ppm	Na2Cr2O7	GD1-18	NA	fetal blood	5	3.63 ± 0.438
	dw	10	ppm	K2Cr2O7	GD1-18	NA	fetal blood	5	4.14 ± 0.397
	ip	50	mg/kg	Na2Cr2O7	on GD17	24 h	fetal blood	5	12.60 ± 1.391
	ip	50	mg/kg	K2Cr2O7	on GD17	24 h	fetal blood	5	7.64 ± 1.233
									%MN (mean ± se)
	dw	0	ppm	Na2Cr2O7	GD1-18	NA	fetal liver PCE	5	2.81 ± 0.194
	dw	5	ppm	Na2Cr2O7	GD1-18	NA	fetal liver PCE	5	2.41 ± 0.273
	dw	10	ppm	Na2Cr2O7	GD1-18	NA	fetal liver PCE	5	2.66 ± 0.290
	dw	10	ppm	K2Cr2O7	GD1-18	NA	fetal liver PCE	5	2.65 ± 0.43
	ip	50	mg/kg	Na2Cr2O7	on GD17	24 h	fetal liver PCE	5	5.86 ± 0.485
	ip	50	mg/kg	K2Cr2O7	on GD17	24 h	fetal liver PCE	5	4.75 ± 0.336
									MN/1000 NCE
									(mean ± se)
Mouse, B6C3F1, M	dw	0	ppm	Cr(VI)	90 days	NA	blood NCE	5	2.70 ± 0.46
(Na2Cr2O7*2H2O)	dw	22	ppm	Cr(VI)	90 days	NA	blood NCE	5	2.60 ± 0.48
NTP (2007)	dw	44	ppm	Cr(VI)	90 days	NA	blood NCE	5	2.20 ± 0.51
	dw	88	ppm	Cr(VI)	90 days	NA	blood NCE	5	3.70 ± 0.44
	dw	175	ppm	Cr(VI)	90 days	NA	blood NCE	5	2.50 ± 0.42
	dw	350	ppm	Cr(VI)	90 days	NA	blood NCE	5	2.00 ± 0.52
									(mean ± se)
Mouse, B6C3F1, F	dw	0	ppm	Cr(VI)	90 days	NA	blood NCE	5	1.70 ± 0.37
(Na2Cr2O7*2H2O)	dw	22	ppm	Cr(VI)	90 days	NA	blood NCE	5	1.20 ± 0.34
NTP (2007)	dw	44	ppm	Cr(VI)	90 days	NA	blood NCE	5	1.60 ± 0.29
	dw	88	ppm	Cr(VI)	90 days	NA	blood NCE	5	1.80 ± 0.30
	dw	175	ppm	Cr(VI)	90 days	NA	blood NCE	5	2.10 ± 0.37
	dw	350	ppm	Cr(VI)	90 days	NA	blood NCE	5	1.90 ± 0.24
									(mean ± se)
Mouse, B6C3F1, M	dw	0	ppm	Cr(VI)	90 days	NA	blood NCE	5	2.20 ± 0.58
(Na2Cr2O7*2H2O)	dw	22	ppm	Cr(VI)	90 days	NA	blood NCE	5	3.20 ± 0.41
NTP (2007)	dw	44	ppm	Cr(VI)	90 days	NA	blood NCE	5	3.00 ± 0.16
	dw	88	ppm	Cr(VI)	90 days	NA	blood NCE	5	3.80 ± 0.37
									(mean ± se)
Mouse, BALB/c, M	dw	0	ppm	Cr(VI)	90 days	NA	blood NCE	5	4.70 ± 0.46
(Na2Cr2O7*2H2O)	dw	22	ppm	Cr(VI)	90 days	NA	blood NCE	5	3.90 ± 0.48
NTP (2007)	dw	44	ppm	Cr(VI)	90 days	NA	blood NCE	5	3.30 ± 0.80
	dw	88	ppm	Cr(VI)	90 days	NA	blood NCE	5	4.20 ± 0.34
									(mean ± se)
Mouse, am3-C57BL/6, M	dw	0	ppm	Cr(VI)	90 days	NA	blood NCE	10	1.65 ± 0.24
(Na2Cr2O7*2H2O)	dw	22	ppm	Cr(VI)	90 days	NA	blood NCE	10	2.50 ± 0.17
NTP (2007)	dw	44	ppm	Cr(VI)	90 days	NA	blood NCE	10	3.05 ± 0.26
	dw	88	ppm	Cr(VI)	90 days	NA	blood NCE	9	3.72 ± 0.53
									MN/2000 PCE
									(mean ± sd)
Mouse, CD-1, M	ip	0	mg/kg	CrO3	1 day	24 h	blood PCE	5	0.8 ± 0.8
(CrO3)	ip	20	mg/kg	CrO3	1 day	24 h	blood PCE	5	3.0 ± 1.6
Garcia-Rodriguez et al. (2013)	ip	0	mg/kg	CrO3	1 day	48 h	blood PCE	5	1.2 ± 0.8
	ip	20	mg/kg	CrO3	1 day	48 h	blood PCE	5	13.2 ± 3.8
	ip	0	mg/kg	CrO3	1 day	72 h	blood PCE	5	1.6 ± 1.5
	ip	20	mg/kg	CrO3	1 day	72 h	blood PCE	5	3.4 ± 1.1
									%MN (mean ± se)
Rat, Sprague-Dawley, M	dw	0	ppm	Cr(VI)	6 months		erythrocytes	5	0
(Na2Cr2O7*2H2O)	dw	182	ppm	Cr(VI)	6 months		erythrocytes	5	4 ± 0.003
Elshazly et al. (2016)

^aafter last exposure

CA: chromosomal aberration; dw: drinking water; F: female; geo: geometric; ip: intraperitoneal; it: intratracheal; iv: intravenous; KN: karyorrhectic nucleus; M: male; MF: mutant frequency; MN: micronucleus; mg/kg: milligrams per kilogram; n: number of animals; NA: not available; NCE: normochromatic erythrocytes; PCE: polychromatic erythrocytes; po: oral gavage; ppm: parts per million; sd: standard deviation.

Bolded values differ significantly from control.

Table 3. Summary of in vivo DNA damage assays on Cr(VI).

Species/Strain/Sex	Route	Dose	Units	Test Article	Duration/Frequency	Analysis Time	Tissue	n	Endpoint	Results
										mean ± sd
Rat, Sprague-Dawley, F	po	0	mg/kg	Na2Cr2O7*2H2O	1 day	48 h	liver	4-6	DNA elution constant (x10^3)	4.6 ± 0.9
(Na2Cr2O7*2H2O, CrCl3)	po	25	mg/kg	Na2Cr2O7*2H2O	1 day	48 h	liver	4-6	DNA elution constant (x10^3)	7.6 ± 0.6
Bagchi, Hassoun, Bagchi, Stohs et al. (1995)	po	895	mg/kg	CrCl3	1 day	48 h	liver	4-6	DNA elution constant (x10^3)	6.9 ± 0.7
										mean ± sd
Rat, Sprague-Dawley, F	po	0	mg/kg	Na2Cr2O7*2H2O	15 day	NA	liver	4-6	DNA elution constant (x10^-3)	4.2 ± 0.5
(Na2Cr2O7*2H2O)	po	10	mg/kg	Na2Cr2O7*2H2O	15 day	NA	liver	4-6	DNA elution constant (x10^-3)	6.3 ± 0.2
Bagchi, Hassoun, Bagchi, Muldoon et al. (1995)	po	0	mg/kg	Na2Cr2O7*2H2O	30 day	NA	liver	4-6	DNA elution constant (x10^-3)	4.6 ± 0.9
	po	10	mg/kg	Na2Cr2O7*2H2O	30 day	NA	liver	4-6	DNA elution constant (x10^-3)	24.0 ± 1.2
	po	0	mg/kg	Na2Cr2O7*2H2O	45 day	NA	liver	4-6	DNA elution constant (x10^-3)	9.0 ± 0.9
	po	10	mg/kg	Na2Cr2O7*2H2O	45 day	NA	liver	4-6	DNA elution constant (x10^-3)	21.0 ± 3.7
	po	0	mg/kg	Na2Cr2O7*2H2O	60 day	NA	liver	4-6	DNA elution constant (x10^-3)	8.4 ± 0.5
	po	10	mg/kg	Na2Cr2O7*2H2O	60 day	NA	liver	4-6	DNA elution constant (x10^-3)	24.0 ± 1.5
	po	0	mg/kg	Na2Cr2O7*2H2O	75 day	NA	liver	4-6	DNA elution constant (x10^-3)	8.8 ± 0.8
	po	10	mg/kg	Na2Cr2O7*2H2O	75 day	NA	liver	4-6	DNA elution constant (x10^-3)	21.0 ± 5.0
	po	0	mg/kg	Na2Cr2O7*2H2O	90 day	NA	liver	4-6	DNA elution constant (x10^-3)	8.4 ± 1.0
	po	10	mg/kg	Na2Cr2O7*2H2O	90 day	NA	liver	4-6	DNA elution constant (x10^-3)	22.0 ± 3.0
										mean ± sd
Rat, Sprague-Dawley, F	po	0	mg/kg	Na2Cr2O7*2H2O	15, 30, 45, 60, 75 days	NA	liver	4-6	DNA elution constant (x10^-3)	NA
(Na2Cr2O7*2H2O) Bagchi et al. (1997)	po	2.5	mg/kg	Na2Cr2O7*2H2O	15, 30, 45, 60, 75 days	NA	liver	4-6	DNA elution constant (x10^-3)	pos
										mean ± sd
Rat, Sprague-Dawley, M	it	saline	mg/kg	saline	3 days	24 h	lung		% DNA <6kb	9.2 ± 4.2
(Na2Cr2O7*2H2O)	it	2.5	mg/kg	Na2Cr2O7*2H2O	3 days	24 h	lung		% DNA <6kb	30.5 ± 9.7
Izzotti et al. (1998)	it	saline	mg/kg	saline	3 days	24 h	liver		% DNA <6kb	13.5 ± 3.1
	it	2.5	mg/kg	Na2Cr2O7*2H2O	3 days	24 h	liver		% DNA <6kb	10.1 ± 2.2
										mean ± sd
Mice, Swiss-Albino, M	po	0	mg/kg	K2Cr2O7	1 day	1-4, 7, 14 days	leukocytes	5	mean tail length	NA
(K2Cr2O7)	po	0.59	mg/kg	K2Cr2O7	1 day	1-4, 7, 14 days	leukocytes	5	mean tail length	pos
Dana Devi et al. (2001)	po	1.19	mg/kg	K2Cr2O7	1 day	1-4, 7, 14 days	leukocytes	5	mean tail length	pos
	po	2.38	mg/kg	K2Cr2O7	1 day	1-4, 7, 14 days	leukocytes	5	mean tail length	pos
	po	4.75	mg/kg	K2Cr2O7	1 day	1-4, 7, 14 days	leukocytes	5	mean tail length	pos
	po	9.5	mg/kg	K2Cr2O7	1 day	1-4, 7, 14 days	leukocytes	5	mean tail length	pos
	po	19	mg/kg	K2Cr2O7	1 day	1-4, 7, 14 days	leukocytes	5	mean tail length	pos
	po	38	mg/kg	K2Cr2O7	1 day	1-4, 7, 14 days	leukocytes	5	mean tail length	pos
	po	76	mg/kg	K2Cr2O7	1 day	1-4, 7, 14 days	leukocytes	5	mean tail length	pos
	ip	25	mg/kg	cyclophosphamide	1 day	4 h	leukocytes	5	mean tail length	pos
										mean ± se
Mouse, Albino ddYY, M	ip	0	mg/kg	K2Cr2O7	1 day	15 min	liver	5	migration (um)	1.38 ± 1.28
(K2Cr2O7)	ip	20	mg/kg	K2Cr2O7	1 day	15 min	liver	5	migration (um)	13.43 ± 8.06
Ueno et al. (2001)	ip	20	mg/kg	K2Cr2O7	1 day	3 h	liver	5	migration (um)	1.38 ± 0.16
	ip	20	mg/kg	K2Cr2O7	1 day	24 h	liver	5	migration (um)	1.95 ± 0.69
	ip	0	mg/kg	K2Cr2O7	1 day	15 min	kidney	5	migration (um)	1.53 ± 0.46
	ip	20	mg/kg	K2Cr2O7	1 day	15 min	kidney	5	migration (um)	9.39 ± 2.92
	ip	20	mg/kg	K2Cr2O7	1 day	3 h	kidney	5	migration (um)	4.01 ± 1.23
	ip	20	mg/kg	K2Cr2O7	1 day	24 h	kidney	5	migration (um)	1.29 ± 0.16
	ip	0	mg/kg	K2Cr2O7	1 day	15 min	spleen	5	migration (um)	0.57 ± 0.2
	ip	20	mg/kg	K2Cr2O7	1 day	15 min	spleen	5	migration (um)	0.93 ± 0.32
	ip	20	mg/kg	K2Cr2O7	1 day	3 h	spleen	5	migration (um)	1.63 ± 0.78
	ip	20	mg/kg	K2Cr2O7	1 day	24 h	spleen	5	migration (um)	1.19 ± 0.71
	ip	0	mg/kg	K2Cr2O7	1 day	15 min	lung	5	migration (um)	2.47 ± 1.22
	ip	20	mg/kg	K2Cr2O7	1 day	15 min	lung	5	migration (um)	6.84 ± 4.85
	ip	20	mg/kg	K2Cr2O7	1 day	3 h	lung	5	migration (um)	3.98 ± 0.62
	ip	20	mg/kg	K2Cr2O7	1 day	24 h	lung	5	migration (um)	3.88 ± 2.20
	ip	0	mg/kg	K2Cr2O7	1 day	15 min	brain	5	migration (um)	0.64 ± 0.34
	ip	20	mg/kg	K2Cr2O7	1 day	15 min	brain	5	migration (um)	1.59 ± 1.49
	ip	20	mg/kg	K2Cr2O7	1 day	3 h	brain	5	migration (um)	0.93 ± 0.44
	ip	20	mg/kg	K2Cr2O7	1 day	24 h	brain	5	migration (um)	1.37 ± 0.64
										mean ± se
Mouse, ddYY, M	ip	0	mg/kg	K2Cr2O7	1 day		stomach	4	migration (um)	3.66 ± 0.71
(K2Cr2O4)	ip	120	mg/kg	K2Cr2O7	1 day	3 h	stomach	4	migration (um)	21.7 ± 0.84
Sekihashi et al. (2001)	ip	120	mg/kg	K2Cr2O7	1 day	8 h	stomach	4	migration (um)	25.0 ± 0.93
	ip	120	mg/kg	K2Cr2O7	1 day	24 h	stomach	4	migration (um)	8.62 ± 1.52
	po	320	mg/kg	K2Cr2O7	1 day	3 h	stomach	4	migration (um)	10.6 ± 2.18
	po	320	mg/kg	K2Cr2O7	1 day	8 h	stomach	4	migration (um)	15.1 ± 2.91
	po	320	mg/kg	K2Cr2O7	1 day	24 h	stomach	4	migration (um)	7.58 ± 1.04
	ip	0	mg/kg	K2Cr2O7	1 day		colon	4	migration (um)	6.47 ± 1.16
	ip	120	mg/kg	K2Cr2O7	1 day	3 h	colon	4	migration (um)	21.8 ± 3.69
	ip	120	mg/kg	K2Cr2O7	1 day	8 h	colon	4	migration (um)	22.7 ± 5.89
	ip	120	mg/kg	K2Cr2O7	1 day	24 h	colon	4	migration (um)	13.0 ± 1.99
	po	320	mg/kg	K2Cr2O7	1 day	3 h	colon	4	migration (um)	19.9 ± 2.51
	po	320	mg/kg	K2Cr2O7	1 day	8 h	colon	4	migration (um)	26.5 ± 3.56
	po	320	mg/kg	K2Cr2O7	1 day	24 h	colon	4	migration (um)	8.35 ± 1.51
	ip	0	mg/kg	K2Cr2O7	1 day		liver	4	migration (um)	2.50 ± 0.85
	ip	120	mg/kg	K2Cr2O7	1 day	3 h	liver	4	migration (um)	7.07 ± 1.75
	ip	120	mg/kg	K2Cr2O7	1 day	8 h	liver	4	migration (um)	2.81 ± 0.87
	ip	120	mg/kg	K2Cr2O7	1 day	24 h	liver	4	migration (um)	2.14 ± 1.03
	po	320	mg/kg	K2Cr2O7	1 day	3 h	liver	4	migration (um)	2.99 ± 0.49
	po	320	mg/kg	K2Cr2O7	1 day	8 h	liver	4	migration (um)	9.39 ± 2.4
	po	320	mg/kg	K2Cr2O7	1 day	24 h	liver	4	migration (um)	5.06 ± 0.39
	ip	0	mg/kg	K2Cr2O7	1 day		kidney	4	migration (um)	1.62 ± 0.63
	ip	120	mg/kg	K2Cr2O7	1 day	3 h	kidney	4	migration (um)	4.62 ± 1.05
	ip	120	mg/kg	K2Cr2O7	1 day	8 h	kidney	4	migration (um)	3.28 ± 1.13
	ip	120	mg/kg	K2Cr2O7	1 day	24 h	kidney	4	migration (um)	2.17 ± 0.35
	po	320	mg/kg	K2Cr2O7	1 day	3 h	kidney	4	migration (um)	9.60 ± 3.27
	po	320	mg/kg	K2Cr2O7	1 day	8 h	kidney	4	migration (um)	13.8 ± 2.07
	po	320	mg/kg	K2Cr2O7	1 day	24 h	kidney	4	migration (um)	1.21 ± 0.08
	ip	0	mg/kg	K2Cr2O7	1 day		bladder	4	migration (um)	5.67 ± 1.65
	ip	120	mg/kg	K2Cr2O7	1 day	3 h	bladder	4	migration (um)	25.5 ± 2.24
	ip	120	mg/kg	K2Cr2O7	1 day	8 h	bladder	4	migration (um)	23.3 ± 6.26
	ip	120	mg/kg	K2Cr2O7	1 day	24 h	bladder	4	migration (um)	7.13 ± 1.64
	po	320	mg/kg	K2Cr2O7	1 day	3 h	bladder	4	migration (um)	20.3 ± 2.31
	po	320	mg/kg	K2Cr2O7	1 day	8 h	bladder	4	migration (um)	15.7 ± 2.41
	po	320	mg/kg	K2Cr2O7	1 day	24 h	bladder	4	migration (um)	6.48 ± 0.55
	ip	0	mg/kg	K2Cr2O7	1 day		lung	4	migration (um)	3.33 ± 1.37
	ip	120	mg/kg	K2Cr2O7	1 day	3 h	lung	4	migration (um)	9.94 ± 0.77
	ip	120	mg/kg	K2Cr2O7	1 day	8 h	lung	4	migration (um)	6.28 ± 1.31
	ip	120	mg/kg	K2Cr2O7	1 day	24 h	lung	4	migration (um)	4.49 ± 0.71
	po	320	mg/kg	K2Cr2O7	1 day	3 h	lung	4	migration (um)	15.7 ± 2.47
	po	320	mg/kg	K2Cr2O7	1 day	8 h	lung	4	migration (um)	18.6 ± 2.55
	po	320	mg/kg	K2Cr2O7	1 day	24 h	lung	4	migration (um)	5.29 ± 1.3
	ip	0	mg/kg	K2Cr2O7	1 day		brain	4	migration (um)	2.50 ± 0.85
	ip	120	mg/kg	K2Cr2O7	1 day	3 h	brain	4	migration (um)	9.08 ± 1.79
	ip	120	mg/kg	K2Cr2O7	1 day	8 h	brain	4	migration (um)	6.01 ± 1.20
	ip	120	mg/kg	K2Cr2O7	1 day	24 h	brain	4	migration (um)	1.78 ± 0.76
	po	320	mg/kg	K2Cr2O7	1 day	3 h	brain	4	migration (um)	4.88 ± 0.69
	po	320	mg/kg	K2Cr2O7	1 day	8 h	brain	4	migration (um)	8.08 ± 1.98
	po	320	mg/kg	K2Cr2O7	1 day	24 h	brain	4	migration (um)	1.24 ± 0.51
										mean ± se
Mouse, Swiss Albino, M	po	0	mg/kg	K2Cr2O7	1 day	unspecified	lymphocytes	5	mean tail moment	2.49 ± 0.07
(K2Cr2O7)	po	25	mg/kg	K2Cr2O7	1 day	unspecified	lymphocytes	5	mean tail moment	3.93 ± 0.21
Wang et al. (2006)	po	50	mg/kg	K2Cr2O7	1 day	unspecified	lymphocytes	5	mean tail moment	3.95 ± 0.17
	po	100	mg/kg	K2Cr2O7	1 day	unspecified	lymphocytes	5	mean tail moment	5.05 ± 0.30
	po	0	mg/kg	K2Cr2O7	5 days	unspecified	lymphocytes	5	mean tail moment	1.84 ± 0.05
	po	25	mg/kg	K2Cr2O7	5 days	unspecified	lymphocytes	5	mean tail moment	2.3 ± 0.11
	po	50	mg/kg	K2Cr2O7	5 days	unspecified	lymphocytes	5	mean tail moment	3.03 ± 0.09
	po	100	mg/kg	K2Cr2O7	5 days	unspecified	lymphocytes	5	mean tail moment	2.68 ± 0.08
										mean ± se
Mouse, Swiss Albino, M	dw	0	ppm	K2Cr2O7	3 days	NA	lymphocytes	4	tail moment	3.14 ± 0.07
(K2Cr2O7)	dw	10	ppm	K2Cr2O7	3 days	NA	lymphocytes	4	tail moment	4.44 ± 0.34
Kumar et al. (2009)	dw	20	ppm	K2Cr2O7	3 days	NA	lymphocytes	4	tail moment	4.86 ± 0.6
	dw	50	ppm	K2Cr2O7	3 days	NA	lymphocytes	4	tail moment	8.32 ± 0.50
	dw	0	ppm	K2Cr2O7	3 days	NA	lymphocytes	4	tail DNA %	11.49 ± 0.37
	dw	10	ppm	K2Cr2O7	3 days	NA	lymphocytes	4	tail DNA %	13.95 ± 0.83
	dw	20	ppm	K2Cr2O7	3 days	NA	lymphocytes	4	tail DNA %	13.31 ± 0.65
	dw	50	ppm	K2Cr2O7	3 days	NA	lymphocytes	4	tail DNA %	14.20 ± 0.88
	dw	0	ppm	K2Cr2O7	3 days	NA	lymphocytes	4	tail length	35.93 ± 0.35
	dw	10	ppm	K2Cr2O7	3 days	NA	lymphocytes	4	tail length	63.74 ± 2.87
	dw	20	ppm	K2Cr2O7	3 days	NA	lymphocytes	4	tail length	86.21 ± 10.87
	dw	50	ppm	K2Cr2O7	3 days	NA	lymphocytes	4	tail length	139.75 ± 4.80
										mean ± sd
Rat, Sprague-Dawley, M	ip	0	mg/kg	K2Cr2O7	5 days	24, 48, 96, 72 h	lymphocytes	5	mean tail length	NA
(K2Cr2O7)	ip	2.5	mg/kg	K2Cr2O7	5 days	24, 48, 96, 72 h	lymphocytes	5	mean tail length	neg, 24-96
Patlolla et al. (2009)	ip	5	mg/kg	K2Cr2O7	5 days	24, 48, 96, 72 h	lymphocytes	5	mean tail length	neg, 24-96
	ip	7.5	mg/kg	K2Cr2O7	5 days	24, 48, 96, 72 h	lymphocytes	5	mean tail length	pos, 24-48
	ip	10	mg/kg	K2Cr2O7	5 days	24, 48, 96, 72 h	lymphocytes	5	mean tail length	pos, 24-48
										mean ± se
Rat, Sprague-Dawley, M	dw	0	ppm	Cr(VI)	6 months	NA	liver		tail DNA %	8.67 ± 0.49
(Na2Cr2O7*2H2O)	dw	182	ppm	Cr(VI)	6 months	NA	liver		tail DNA %	30.09 ± 2.21
Elshazly et al. (2016)	dw	0	ppm	Cr(VI)	6 months	NA	liver		tail length	18.88 ± 0.87
	dw	182	ppm	Cr(VI)	6 months	NA	liver		tail length	27.08 ± 1.78

dw: drinking water; F: female; ip: intraperitoneal; it: intratracheal; M: male; mg/kg: milligrams per kilogram; n: number of animals, NA: not available; po: oral gavage; ppm: parts per million; sd: standard deviation; se: standard error.

Bolded values differ significantly from control.

Figure 4. Summary of in vivo Cr(VI) mutation assays employing drinking water exposure. Red triangles indicate data points that differed significantly from concurrent controls. For clarity, variance data have been removed. The dotted line marks the current MCL of 0.1 ppm total Cr. Text on each plot designates the tissue examined, duration of exposure, and gene measured. Source: (A, B): Thompson Young et al. (2015); (C) Thompson et al. (2017); (D) O’Brien et al. (2013); (E,F) Aoki et al. (2019); (G) Kirpnick-Sobel et al. (2006).

Figure 5. Summary of in vivo Cr(VI) MN assays in the female B6C3F1 mouse duodenum. Red triangles indicate data points that differed significantly form concurrent controls. For clarity, variance data have been removed. The dotted line marks the current MCL of 0.1 ppm total Cr. Text on each plot designates the tissue examined and duration of exposure. Source: (A, C): EPL (2013); (B, D, F) O’Brien et al. (2013); (E) Thompson et al. (2015).

Figure 6. Summary of in vivo Cr(VI) MN assays in blood and bone marrow drinking water studies. Red triangles indicate data points that differed significantly form concurrent controls. For clarity, variance data have been removed. The dotted line marks the current MCL of 0.1 ppm total Cr. Source: (A-B) Mirsalis et al. (1996); (C–F) De Flora et al. (2006); (G–K) NTP (2007); (L) Elshazly et al. (2016).

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