Dose-response for assessing the cancer risk of inorganic arsenic in drinking water: the scientific basis for use of a threshold approach

Figures & data

Figure 1. Metabolism of inorganic arsenic through progressive reductions and then oxidative methylations. The trivalent forms can react with sulfhydryl groups producing biologic effects. Although formation of TMA^VO readily occurs in rodents, its formation is limited in humans unless exposed to very high (toxic) levels of inorganic arsenic.

Figure 2. Dimethylarsinic acid (DMA^V) can be derived from numerous starting arsenicals. The DMA^V is excreted predominantly in the urine. At high exposures of inorganic arsenic in the drinking water, most of the urinary DMA^V is derived from the inorganic arsenic. However, at low exposure levels in the drinking water, these other sources of DMA^V, primarily from food sources, will predominate.

Figure 3. Inorganic arsenic can be metabolized to thioarsenicals and methylated arsenicals. Ultimately trivalent arsenicals are generated inside the cell that can react with sulfhydryl groups. Reaction with critical cellular proteins will produce biologic effects. These effects are all non-cancerous. However, the cytotoxicity produced in epithelial cells, such as skin, lung, and urinary bladder, will lead to regenerative cell proliferation. If prolonged, this ultimately leads to an increased risk of these cancers.

Table 1. Dose-response for the in vitro effects of arsenic in primary cells.

Updated from Gentry et al. 2010.

Gene Expression: ▪ Decreases □ Increases.

*Protein.

**Notation for fibroblasts.

NOTE: Empty cells do not indicate a lack of studies conducted at that concentration range; rather, they indicate no significant changes in up or down-regulation of genes or proteins evaluated. Studies are categorized into specific concentrations. The actual range of concentrations is provided in footnotes.

¹Administration of 0.005 to 0.01 μM included.

²(Hamadeh et al. 2002).

³(Parrish et al. 1999).

⁴Administration of 0.1 to 0.5 μM included.

⁵(Vogt and Rossman 2001).

⁶(Liao et al. 2004).

⁷Administration of 1.0 to 2.5 μM included.

⁸(Sturlan et al. 2003).

⁹(Hirano et al. 2003).

¹⁰(Wijeweera et al. 2001).

¹¹(Kao et al. 2003).

¹²(Wang and Proud 1997).

¹³(Shimizu et al. 1998).

¹⁴(Lau et al. 2004).

¹⁵(Yih and Lee 2000).

¹⁶Administration of 6 to 13 μM included.

¹⁷(Jaspers et al. 1999).

¹⁸(Rea et al. 2003).

¹⁹(Namgung and Xia 2001).

²⁰(Barchowsky et al. 1999).

²¹Administration of 30 to 100 μM included.

²²(Garrett et al. 2001).

²³(Mengesdorf et al. 2002).

Table 2. Benchmark dose ranges for genes with a statistically significant dose-response trend in primary urothelial cells from most subjects after treatment with arsenite, MMA^III, and DMA^III (trivalent) mixtures.

Gene Name	Description	Number of subjects expressing the gene/total subjects	BMD range (µM)	BMDL range (µM)
HMOX1	Oxidative stress response	10/10	0.13–0.50	0.09–0.33
FKBP5	Protein folding	9/10	0.36–0.92	0.24–0.58
TXNRD1	Thioredoxin reductase	9/10	0.32–0.75	0.21–0.48
MT1E	Metallothionine regulation	8/10	0.24–0.77	0.16–0.49
DDB2	DNA damage sensing	8/10	0.30–0.88	0.20–0.56
TXN	Thioredoxin	8/10	0.26–0.76	0.17–0.48
LGALS8	Cell adhesion, growth regulation	8/10	0.16–0.92	0.11–0.58
THBD	Immune response	8/10	0.32–0.90	0.20–0.57

Table 3. Studies of low-level arsenic exposure* included in the main evaluation of dose-response in the current study in comparison to Lynch et al. (2017a) and non-ecological studies in Lamm et al. (2015) and Tsuji, Alexander et al. (2014).

Study (cancer type)	Location	Lynch et al. (2017a)	Lamm et al. (2015)	Tsuji, Alexander et al. (2014)	Current Study	Reason for exclusion from primary analysis or for update of Lynch et al. (2017a)
Baris et al. (2016) (bladder)	U.S.	yes	no	no	yes
Bates et al. (1995) (bladder)	U.S.	no	no	yes	no	Cumulative dose in mg or mg/L-years
Bates et al. (2004) (bladder)	U.S.	yes	no	yes	yes
Chen et al. (2010a) (bladder)	NE Taiwan	yes	no	yes	yes
Ferreccio et al. (2013) (bladder, lung)	Chile	no	yes	no	no	Same data as in Steinmaus et al. (2013); adjusted odds ratios only for smokers or never smokers
Karagas et al. (2004) (bladder)	U.S.	no	no	yes	yes	Excluded by Lynch et al. (2017a) because of toenail biomarker; included based on published quantitative relationship with arsenic in drinking water, enabling conversion (see Supplemental Information 2)
Kurttio et al. (1999) (bladder)	Finland	yes	no	yes	yes
Lewis et al. (1999) (bladder, lung)	U.S.	no	no	yes	no	Cumulative dose in mg/L-years
Meliker et al. (2010) (bladder)	U.S.	yes	no	yes	yes
Michaud et al. (2004) (bladder)	Finland	no	no	yes	no	Toenail biomarker with no population-specific conversion to other measures of exposure
Mostafa and Cherry (2015) (bladder)	Bangladesh	yes	no	no	yes
Steinmaus et al. (2003) (bladder)	U.S.	no	no	yes	no	Cumulative dose in mg
Steinmaus et al. (2013) (bladder, lung)	Chile	yes	no	no	yes
Chen et al. (2010b) (lung)	NE Taiwan	yes	yes	no	yes
Dauphine et al. (2013) (lung)	U.S.	yes	yes	no	yes
D’Ippoliti et al. (2015) (lung)	Italy	yes	no	no	no	No individual-level adjustment for smoking; Lynch et al. (2017a) did not include in meta-regression analysis
Mostafa et al. (2008) (lung)	Bangladesh	Yes (smoking, nonsmoking males)	no	no	Yes (nonsmoking males)	Data for males stratified by smoking status; results in smokers probably confounded and include effect modification; data for females not stratified or adjusted for smoking
Smith et al. (2009) (lung)	Chile	yes	yes	no	yes

*Excludes Chiou et al. (1995), Huang et al. (2008), and Wang, Yeh, et al. (2009), which were included in Lynch et al. (2017a) but pertain to high-level arsenic exposure >150 µg/L.

Table 4. Studies included in the current dose-response evaluation of arsenic water concentration and bladder cancer risk.

Study (location)	Study design	Exposure concentration group (µg/L)	Approximate highest concentration* (µg/L)	Dose measure	Water intake rate (L/day)	Adjusted exposure midpoint (µg/L)^†	RR	95% CI	# of cases/non-cases
Baris et al. (2016)(ME, NH, VT, U.S.)	Case-control	≤0.5	<100	Average lifetime	1.5‡	0.19	1.00		303/325
		>0.5−1.0				0.56	0.77	0.60−0.98	226/318
		>1.0−2.1				1.16	0.97	0.76−1.24	281/323
		>2.1−7.0				3.41	0.98	0.74−1.28	225/259
		>7.0−10.4				6.53	0.64	0.33−1.23	18/30
		>10.4				11.70	1.10	0.61−2.00	26/32
Bates et al. (2004)(Argentina)	Case-control	0−50	200	Average lifetime, excluding proxy wells	2.28¶	28.50	1.00		87/80
		51−100				86.07	1.11	0.3−3.7	8/8
		101−200				171.57	0.81	0.3−2.0	13/13
Chen et al. (2010a)(NE Taiwan)	Prospective cohort	<10	<100	Most recent well concentration	2.75§	9.63	1.00^‖		5/2283
		10−49.9				57.75	1.66	0.53−5.21	8/2085
		50−99.9				144.38	2.42	0.69−8.54	5/902
Karagas et al. (2004)(NH, U.S.)	Case-control	0−0.0001#	100**	Water concentration based on toenails	1.5††	0.00004	1.00		90/162
		0.0002−0.47				0.18	1.37	0.96−1.96	119/162
		0.60−3.07				1.38	1.08	0.74−1.58	88/157
		3.14−10.01				4.93	1.04	0.66−1.63	48/96
		10.16−27.24				14.03	1.33	0.71−2.49	21/32
		27.51−44.24				26.91	0.41	0.11−1.50	3/13
		≥44.61				50.19	1.36	0.63−2.90	14/19
Kurttio et al. (1999)(Finland)	Case-cohort	<0.1	64	Average 10 years and earlier; wells sampled in 1996	1.6‡‡	0.04	1.00		26/137¶¶
		0.1−0.5				0.24	0.81	0.41−1.63	18/69
		≥0.5				0.60	1.51	0.67−3.38	17/69
Meliker et al. (2010)(MI, U.S.)	Case-control	<1	<100	Average lifetime using current water data and geospatial modeling for past locations	1‡	0.25	1.00		187/264
		1−10				2.75	0.84	0.63−1.12	182/180
		>10				7.50	1.10	0.65−1.86	38/37
Mostafa and Cherry (2015)(Bangladesh)	Case-referent	<10	200	Mean of wells in the district of residence at time of biopsy	3.0§§	8.75	1.00		238/206
		10−50				52.5	1.52	1.08−2.14	319/190
		50−100				131.25	1.07	0.73−1.57	204/145
		100−200
Steinmaus et al. (2013)(northern Chile)	Case-control	<26	197	Average lifetime	1.8‖‖	11.7	1.00		33/202
		26−79				47.25	0.92	0.52−1.61	33/189
		80−197				124.65	2.62	1.53−4.50	71/142

RR: Relative risk; CI: Confidence interval.

* Estimate of highest dose measure (e.g., average lifetime exposure, etc.) of participants in the study.

† Midpoint exposure concentration × water intake/2 L/day.

‡ Median for study population.

¶ Mean residential intake for controls.

§ Default assumption for Taiwan; midpoint exposure also multiplied by 70 kg/50 kg to adjust for smaller body weight (Lynch et al. 2017a).

‖ All urinary cancers, including urothelial carcinoma, non-urothelial carcinoma, and urinary cancer in the renal pelvis (ICD-9 code 189.1).

# Converted from toenail concentration ranges of 0.009–0.059, 0.060–0.086, 0.087–0.126, 0.127–0.193, 0.194–0.277, 0.278–0.330, 0.331–2.484 µg/g based on Karagas et al. (2000) (see Supplemental Information 2).

** Based on sampling reported in Karagas et al. (2000); not all participants’ wells were sampled.

†† Based on Baris et al. (2016).

‡‡ Mean for study population.

¶¶ Numbers of non-cases could not be confirmed; as reported by Lynch et al. (2017a).

§§ Default assumption for Bangladesh; midpoint exposure also multiplied by 70 kg/60 kg to adjust for smaller body weight (Lynch et al. 2017a).

‖‖ Mean for controls 20 years ago (Steinmaus et al. 2013) or mean of current and 20 years ago for controls exposed to <100 µg/L (Steinmaus, Ferreccio, Yuan et al. 2014).

Table 5. Studies included in the current dose-response evaluation of arsenic water concentration and lung cancer risk.

Study (location)	Study design	Exposure concentration group (µg/L)	Approximate highest concentration* (µg/L)	Dose measure	Water intake rate (L/day)	Adjusted exposure midpoint (µg/L)†	RR	95% CI	# of cases/non-cases
Dauphine et al. (2013) (CA, NV, U.S.)	Case-control	≤10	3 individuals with historical exposure >110; maximum 1,460	Highest 5-year average, 10-year lag	2.12‡	5.3	1.00		141/241
		11−84				50.35	0.75	0.45−1.25	37/82
		≥85				135.15	0.84	0.41−1.72	18/36
Chen et al. (2010b) (NE Taiwan)	Prospective cohort	<10	<100	Most recent well concentration	2.75¶	9.625	1.00		48/2240§
		10−49.9				57.75	1.10	0.74−1.63	51/2042
		50−99.9				144.375	0.99	0.59−1.68	20/887
Mostafa et al. (2008) nonsmoking males (Bangladesh)	Case-referent	0−10	100	Mean of wells in the district of residence at time of biopsy	3.0‖	8.75	1.00	1.00	85/69
		11−50				52.5	0.90	0.62−1.33	241/208
		51−100				131.25	1.10	0.62−1.96	45/33
Smith et al. (2009) (northern Chile)	Case-control	0−9	199	Average water concentration during peak period 1958−1970	1.8#	4.5**	1.0		11/92
		10−59				31.5	0.7	0.3−1.7	7/81
		60−199				117	3.4	1.8−6.5	35/87
Steinmaus et al. (2013) (northern Chile)	Case-control	<26	197	Average lifetime	1.8#	11.7	1.00		61/202
		26−79				47.25	0.98	0.62−1.53	61/189
		80−197				124.65	1.70	1.05−2.75	85/142

RR: Relative risk; CI: Confidence interval.

* Estimate of highest dose measure (e.g., average lifetime exposure) of participants in the study.

† Midpoint exposure concentration × water intake/2 L/day.

‡ Mean of water intake for controls currently, 20, and 40 years ago (Lynch et al. 2017a).

¶ Default assumption for Taiwan; midpoint exposure also multiplied by 70 kg/50 kg to adjust for lower average body weight (Lynch et al. 2017a).

§ Number of non-cases based on total numbers per group reported by Chen et al. (2010a).

‖ Default assumption for Bangladesh; midpoint exposure also multiplied by 70 kg/60 kg to adjust for lower average body weight (Lynch et al. 2017a).

# Mean for controls 20 years ago (Steinmaus et al. (2013) or mean of current and 20 years ago for controls exposed to <100 µg/L (Steinmaus, Ferreccio, Yuan et al. 2014).

** Midpoint before adjustment based on study-reported group mean concentrations (5, 35, 130 µg/L).

Figure 4. Relative risks (95% confidence intervals) of bladder cancer at low-level average arsenic water concentrations (a. <12 µg/L; b. <180 µg/L).

Figure 5. Relative risks (95% confidence intervals) of lung cancer at low-level average arsenic water concentrations.

Figure 6. Odds ratios (except as noted) for lung and bladder cancer at low-level arsenic exposures reported for never smokers. *Converted from toenail concentration ranges based on Karagas et al. (2000) (see Table 6).

Table 6. Results of epidemiological studies of low-level arsenic exposure and risk of bladder or lung cancer among never smokers. Results in italics are not directly relevant to the dose-response assessment of low-level drinking water arsenic and bladder or lung cancer risk but are included for completeness.

Study (location)	Cancer	Exposure category	OR	95% LCL	95% UCL
Bates et al. (1995)	Bladder	<19 mg cumulative*	1.00	(reference)
(UT, U.S.)		19 to <33 mg cumulative	1.09	0.4	3.1
		33 to <53 mg cumulative	0.68	0.2	2.3
		≥53 mg cumulative	0.53	0.1	1.9
		<33 mg/L-y	1.00	(reference)
		33 to <53 mg/L-y	0.21	0.1	0.8
		53 to <74 mg/L-y	0.25	0.1	0.9
		≥74 mg/L-y	0.91	0.3	3.2
Bates et al. (2004)	Bladder	0 to 50 µg/L excl. proxy wells	1.00	(reference)
(Argentina)		51 to 100 µg/L excl. proxy wells	1.05	0.2	6.9
		101 to 200 µg/L excl. proxy wells	1.10	0.2	6.3
		>200 µg/L excl. proxy wells	0.58	0.1	6.2
		0 to 50 µg/L incl. proxy wells	1.00	(reference)
		51 to 100 µg/L incl. proxy wells	0.53	0.1	2.3
		101 to 200 µg/L incl. proxy wells	0.64	0.1	3.1
		>200 µg/L incl. proxy wells	0.25	0.0	2.7
		0 to 0.5 µg/L, fluid-adj., excl. proxy wells	1.00	(reference)
		0.6 to 1.2 µg/L, fluid-adj., excl. proxy wells	2.15	0.4	11
		1.3 to 35 µg/L, fluid-adj., excl. proxy wells	4.03	0.9	18
		>35 µg/L, fluid-adj., excl. proxy wells	2.27	0.4	12
		0 to 1.0 µg/L, fluid-adj., incl. proxy wells†	1.00	(reference)
		1.1 to 17 µg/L, fluid-adj., incl. proxy wells	0.36	0.1	1.7
		18 to 80 µg/L, fluid-adj., incl. proxy wells	0.95	0.2	3.9
		>80 µg/L, fluid-adj., incl. proxy wells	0.59	0.1	2.9
Ferreccio et al. (2013)	Bladder	<11 µg/L before 1971‡	1.00	(reference)
(northern Chile)		11 to 91 µg/L before 1971	2.66	0.91	7.83
(same study population		92 to 335 µg/L before 1971	7.01	2.61	18.82
as Steinmaus et al. 2013)		>335 µg/L before 1971	8.86	2.99	26.23
		0 to 34 µg/L before 1971	1.00	(reference)
		35 to 260 µg/L before 1971	1.92	0.90	4.11
		>260 µg/L before 1971	5.27	2.51	11.07
		0 to 2589 µg/L-y	1.00	(reference)
		2590 to 9915 µg/L-y	3.03	1.28	7.15
		>9915 µg/L-y	8.42	3.60	19.69
Karagas et al. (2004)	Bladder	0.009 to 0.059 µg/g toenail=0 to 0.0001 µg/L	1.00	(reference)
(U.S., NH)		0.060 to 0.086 µg/g toenail=0.0002 to 0.47 µg/L	0.85	0.38	1.91
		0.087 to 0.126 µg/g toenail=0.60 to 3.07 µg/L	1.18	0.53	2.66
		0.127 to 0.193 µg/g toenail=3.14 to 10.01 µg/L	1.10	0.42	2.90
		0.194 to 0.277 µg/g toenail=10.16 to 27.24 µg/L	0.49	0.12	2.01
		0.278 to 0.330 µg/g toenail=27.51 to 44.24 µg/L	(no cases)
		0.331 to 2.484 µg/g toenail=≥44.61 µg/L	(no cases)
Koutros, Baris et al. (2018)	Bladder	0 to 15.70 mg, no lag	1.0	(reference)
(ME, NH, VT, U.S.)		>15.70 to 34.50 mg, no lag	1.2	0.7	2.1
		>34.50 to 77.04 mg, no lag	0.9	0.5	1.5
(same study population		>77.04 mg, no lag	1.1	0.6	1.9
as Baris et al. 2016)		0 to 3.52 mg, 40-y lag¶	1.0	(reference)
		>3.52 to 8.77 mg, 40-y lag	1.0	0.5	1.7
		>8.77 to 22.42 mg, 40-y lag	1.3	0.7	2.3
		>22.42 mg, 40-y lag	1.1	0.6	2.0
Meliker et al. (2010)	Bladder	<1 µg/L ave. lifetime§	1.00	(reference)
(MI, U.S.)		1 to 10 µg/L ave. lifetime	0.72	0.43	1.20
		>10 µg/L ave. lifetime	1.62	0.68	3.87
		<1 µg/day	1.00	(reference)
		1 to 10 µg/day	0.80	0.47	1.35
		>10 µg/day	2.01	0.87	4.68
Mostafa and Cherry	Bladder (urinary tract transition cell carcinoma)	<10 µg/L	1.00	(reference)
(2015)		10 to <50 µg/L	1.67	0.97	2.89
(Bangladesh)		50 to <100 µg/L	1.10	0.61	1.97
		100 to <200 µg/L	0.99	0.58	1.69
		200 to <300 µg/L	2.19	1.20	4.01
		≥300 µg/L	0.65	0.34	1.26
Steinmaus et al. (2003)	Bladder	<10 µg/day highest 1-y ave., 5-y lag	1.00	(reference)
(CA, NV, U.S.)		10–80 µg/day highest 1-y ave., 5-y lag	1.40	0.53	3.69
		>80 µg/day highest 1-y ave., 5-y lag	0.45	0.13	1.64
		<10 µg/day highest 5-y ave., 5-y lag	1.00	(reference)
		10–80 µg/day highest 5-y ave., 5-y lag	0.77	0.29	2.08
		>80 µg/day highest 5-y ave., 5-y lag	0.41	0.12	1.44
		<10 µg/day highest 20-y ave., 5-y lag	1.00	(reference)
		10–80 µg/day highest 20-y ave., 5-y lag	0.54	0.17	1.69
		>80 µg/day highest 20-y ave., 5-y lag	0.51	0.14	1.83
		<6.4 mg cumulative, 5-y lag	1.00	(reference)
		6.4–82.8 mg cumulative, 5-y lag	1.55	0.51	4.72
		>82.8 mg cumulative, 5-y lag	0.83	0.28	2.49
		<10 µg/day highest 1-y ave., 40-y lag	1.00	(reference)
		10–80 µg/day highest 1-y ave., 40-y lag	1.51	0.33	6.99
		>80 µg/day highest 1-y ave., 40-y lag	0.31	0.06	1.66
		<10 µg/day highest 40-y ave., 40-y lag	1.00	(reference)
		10–80 µg/day highest 40-y ave., 40-y lag	2.94	0.56	15.49
		>80 µg/day highest 40-y ave., 40-y lag	0.32	0.06	1.72
		<10 µg/day highest 20-y ave., 40-y lag	1.00	(reference)
		10–80 µg/day highest20-y ave., 40-y lag	0.48	0.05	4.39
		>80 µg/day highest 20-y ave., 40-y lag	0.40	0.07	2.24
		<6.4 mg cumulative, 40-y lag‖	1.00	(reference)
		6.4–82.8 mg cumulative, 40-y lag	2.65	0.49	14.24
		>82.8 mg cumulative, 40-y lag	0.50	0.12	2.05
Steinmaus et al. (2006)	Bladder	<16.7% MMA, Argentina	1.00	(reference)
(U.S. and Argentina)		≥16.7% MMA, Argentina	0.48	0.17	1.33
		<16.7% MMA, <100 µg/day, Argentina#	1.00	(reference)
		≥16.7% MMA, <100 µg/day, Argentina	0.42	0.12	1.44
		<16.7% MMA, ≥100 µg/day, Argentina	1.00	(reference)
		≥16.7% MMA, ≥100 µg/day, Argentina	0.61	0.09	4.26
		<14.9% ave. MMA, U.S.	1.00	(reference)
		≥14.9% ave. MMA, U.S.	4.33	0.21	90.8
Chen et al. (2010b)	Lung	<10 µg/L, all (rate ratio)	1.00	(reference)
(northeast Taiwan)		10 to 99.9 µg/L, all (rate ratio)	1.22	0.64	2.32
		≥100 µg/L, all (rate ratio)	1.32	0.64	2.74
Dauphine et al. (2013)**	Lung	≤10 µg/L highest 5-y ave., 10-y lag	1.00	(reference)
(CA, NV, U.S.)		11 to 84 µg/L highest 5-y ave., 10-y lag	>0.75	(not reported)
		≥85 µg/L highest 5-y ave., 10-y lag	<0.84	(not reported)
		≤10 µg/L highest 5-y ave., 40-y lag	1.00	(reference)
		11 to 84 µg/L highest 5-y ave., 40-y lag	>0.84	(not reported)
		≥85 µg/L highest 5-y ave., 40-y lag	<1.39	(not reported)
		≤0.1 µg/L-y, 10-y lag	1.00	(reference)
		0.11 to 2399 µg/L-y, 10-y lag	>0.75	(not reported)
		≥2400 µg/L-y, 10-y lag	<1.20	(not reported)
Ferreccio et al. (2013)	Lung	<11 µg/L‡	1.00	(reference)
(Northern Chile)		11 to 91 µg/L	0.68	0.29	1.58
(same study population		92 to 335 µg/L	0.93	0.37	2.36
as Steinmaus et al.		>335 µg/L	2.04	0.84	4.95
2013)		0 to 34 µg/L before 1971	1.00	(reference)
		35 to 260 µg/L before 1971	0.87	0.42	1.81
		>260 µg/L before 1971	1.67	0.78	3.56
		0 to 2589 µg/L-y	1.00	(reference)
		2590 to 9915 µg/L-y	1.28	0.59	2.77
		>9915 µg/L-y	2.18	1.01	4.69
Heck et al. (2009)	Lung	<0.05 µg/g toenail	1.00	(reference)
(NH, VT, U.S.)		≥0.05 µg/g toenail	1.03	0.28	3.75
Mostafa et al. (2008)	Lung	0 to≤10 µg/L	1.00	(reference)
(Bangladesh)		11 to≤50 µg/L	0.90	0.62	1.33
		51 to≤100 µg/L	1.10	0.62	1.96
		101 to 400 µg/L	0.94	0.62	1.41

Rationale for selection of results for Figure 6: *mg more often used than mg/L-years; †similar results whether or not fluid-adjusted, including proxy wells, increases sample size; ‡lower-dose group; ¶Baris et al. (2016) reported statistically significant positive results with 40-year lag in this population; §consistency with other studies; ‖consistency with other studies, 40-year lag has higher odds ratio; #low-dose, <100 µg/day adjusted results not available for U.S.; **not included–results for never smokers are inferred based on the overall OR being a weighted average of ORs for smokers and never smokers.

OR: odds ratio (except for Chen et al. [2010b], where the relative risk estimate is a rate ratio); LCL: lower confidence limit; UCL: upper confidence limit.

Table 7. Convergence of evidence: inorganic arsenic.

	Adaptive Effects	Toxicity	Severe Toxicity and Lethality
In vitro As^III concentration	<0.1–0.2 µM (32–65 µg/L in drinking water) Cells in adaptive state; DNA integrity not affected	0.2 to 10 µM (>65 µg/L in drinking water) Adverse responses: up-regulation of DNA repair, telomerase activity, and cell cycle control genes	>10 µM DNA and mitochondria damage; apoptosis; down-regulation of DNA repair genes, cell death
In vivo (animals) iAs^III or iAs^V in diet or water	<10 ppm inorganic As in water or diet No effects on urothelium	≥10 ppm inorganic As in water or diet Cytotoxicity/regenerative proliferation of urothelium	100 ppm is MTD in mice and rats
In vivo (humans) As in drinking water	50 to <100 µg/L in drinking water No clear evidence of increased risk of health effects, particularly for never smokers	150 to >1000 µg/L in drinking water Increasing risk with higher exposures to arsenic in well water	0.11 to 0.16 mg/kg/dayAs2O3 treatment of acute promyelocytic leukemia (PML) Acute and chronic health effects in exposed populations

In vitro effects of trivalent inorganic arsenic and trivalent methylated arsenicals correspond to the systemic and tissue levels in vivo. The amount in the drinking water for humans and the amounts in the drinking water or diet in rodents required to generate the effects in vivo corresponding to the effect in vitro are listed in this table.

As^III: trivalent arsenicals.

iAs^III and iAs^V: inorganic arsenite and arsenate, respectively.

As: inorganic arsenic (trivalent plus pentavalent).

MTD: Maximum Tolerated Dose.

Gentry PR, McDonald TB, Sullivan DE, Shipp AM, Yager JW, Clewell HJ. 2010. Analysis of genomic dose-response information on arsenic to inform key events in a mode of action for carcinogenicity. Environ Mol Mutagen. 51:1–14.

 PubMed Web of Science ®Google Scholar

Hamadeh H, Trouba K, Amin R, Afshari C, Germolec D. 2002. Coordination of altered DNA repair and damage pathways in arsenite-exposed keratinocytes. Toxicol Sci. 69:306–316.

 PubMed Web of Science ®Google Scholar

Parrish A, Zheng X, Turney K, Younis H, Gandolfi A. 1999. Enhanced transcription factor DNA binding and gene expression induced by arsenite or arsenate in renal slices. Toxicol Sci. 50:98–105.

 PubMed Web of Science ®Google Scholar

Vogt B, Rossman T. 2001. Effects of arsenite on p53, p21 and cyclin D expression in normal human fibroblasts - a possible mechanism for arsenite's comutagenicity. Mutat Res. 478:159–168.

 PubMed Web of Science ®Google Scholar

Liao W, Chang K, Yu C, Chen G, Chang L, Yu H. 2004. Arsenic induces human keratinocyte apoptosis by the FAS/FAS ligand pathway, which correlates with alterations in nuclear factor-j B, activator protein-1 activity. J Invest Dermatol. 122:125–129.

 PubMed Web of Science ®Google Scholar

Sturlan S, Baumgartner M, Roth E, Bachleitner-Hofmann T. 2003. Docosahexaenoic acid enhances arsenic trioxide-mediated apoptosis in arsenic trioxide-resistant HL-60 cells. Blood. 101:4990–4997.

 PubMed Web of Science ®Google Scholar

Hirano S, Cui X, Li S, Kanno S, Kobayashi Y, Hayakawa T, Shraim A. 2003. Difference in uptake and toxicity of trivalent and pentavalent inorganic arsenic in rat heart microvessel endothelial cells. Arch Toxicol. 77:305–312.

 PubMed Web of Science ®Google Scholar

Wijeweera J, Gandolfi A, Parrish A, Lantz R. 2001. Sodium arsenite enhances AP-1 and NFjB DNA binding and induces stress protein expression in precision-cut rat lung slices. Toxicol Sci. 61:283–294.

 PubMed Web of Science ®Google Scholar

Kao Y, Yu C, Chang L, Yu H. 2003. Low concentrations of arsenic induce vascular endothelial growth factor and nitric oxide release and stimulate angiogenesis in vitro. Chem Res Toxicol. 16:460–468.

 PubMed Web of Science ®Google Scholar

Wang X, Proud C. 1997. p70 S6 kinase is activated by sodium arsenite in adult rat cardiomyocytes: Roles for phosphatidylinositol 3-kinase and p38 MAP kinase. Biochem Biophys Res Commun. 238:207–212.

 PubMed Web of Science ®Google Scholar

Shimizu M, Hochadel J, Fulmer B, Waalkes M. 1998. Effect of glutathione depletion and metallothionein gene expression on arsenic-induced cytotoxicity and c-myc expression in vitro. Toxicol Sci. 45:204–211.

 PubMed Web of Science ®Google Scholar

Lau A, Li M, Xie R, He Q, Chiu J. 2004. Opposed arsenite-induced signaling pathways promote cell proliferation or apoptosis in cultured lung cells. Carcinogenesis. 25:21–28.

 PubMed Web of Science ®Google Scholar

Yih L, Lee T. 2000. Arsenite induces p53 accumulation through an ATM-dependent pathway in human fibroblasts. Cancer Res. 60:6346–6352.

 PubMed Web of Science ®Google Scholar

Jaspers I, Samet J, Reed W. 1999. Arsenite exposure of cultured airway epithelial cells activates kappaB-dependent interleukin-8 gene expression in the absence of nuclear factor-kappaB nuclear translocation. J Biol Chem. 274:31025–31033.

 PubMed Web of Science ®Google Scholar

Rea M, Gregg J, Qin Q, Phillips M, Rice R. 2003. Global alteration of gene expression in human keratinocytes by inorganic arsenic. Carcinogenesis. 24:747–756.

 PubMed Web of Science ®Google Scholar

Namgung U, Xia Z. 2001. Arsenic induces apoptosis in rat cerebellar neurons via activation of JNK3 and p38 MAP kinases. Toxicol Appl Pharmacol. 174:130–138.

 PubMed Web of Science ®Google Scholar

Barchowsky A, Roussel R, Klei L, James P, Ganju N, Smith K, Dudek E. 1999. Low levels of arsenic trioxide stimulate proliferative signals in primary vascular cells without activating stress effector pathways. Toxicol Appl Pharmacol. 159:65–75.

 PubMed Web of Science ®Google Scholar

Garrett S, Belcastro M, Sens M, Somji S, Sens D. 2001. Acute exposure to arsenite induces metallothionein isoform-specific gene expression in human proximal tubule cells. J Toxicol Environ Health A. 64:343–355.

 PubMed Web of Science ®Google Scholar

Mengesdorf T, Althausen S, Paschen W. 2002. Genes associated with pro-apoptotic and protective mechanisms are affected differently on exposure of neuronal cell cultures to arsenite. No indication for endoplasmic reticulum stress despite activation of grp78 and gadd153 expression. Brain Res Mol Brain Res. 104:227–239.

 PubMedGoogle Scholar

Lynch HN, Zu K, Kennedy EM, Lam T, Liu X, Pizzurro DM, Loftus CT, Rhomberg LR. 2017a. Quantitative assessment of lung and bladder cancer risk and oral exposure to inorganic arsenic: Meta-regression analyses of epidemiological data. Environ Int. 106:178–206.

 PubMed Web of Science ®Google Scholar

Lamm SH, Ferdosi H, Dissen EK, Li J, Ahn J. 2015. A systematic review and meta-regression analysis of lung cancer risk and inorganic arsenic in drinking water. Int J Environ Res Public Health. 12:15498–15515.

 PubMed Web of Science ®Google Scholar

Tsuji JS, Alexander DD, Perez V, Mink PJ. 2014. Arsenic exposure and bladder cancer: quantitative assessment of studies in human populations to detect risks at low doses. Toxicology. 317:17–30.

 PubMed Web of Science ®Google Scholar

Baris D, Waddell R, Beane Freeman LE, Schwenn M, Colt JS, Ayotte JD, Ward MH, Nuckols J, Schned A, Jackson B. 2016. Elevated bladder cancer in northern New England: the role of drinking water and arsenic. J Natl Cancer Inst. 108:5.

 Google Scholar

Bates MN, Smith AH, Cantor KP. 1995. Case-control study of bladder cancer and arsenic in drinking water. Am J Epidemiol. 141:523–530.

 PubMed Web of Science ®Google Scholar

Bates MN, Rey OA, Biggs ML, Hopenhayn C, Moore LE, Kalman D, Steinmaus C, Smith AH. 2004. Case-control study of bladder cancer and exposure to arsenic in Argentina. Am J Epidemiol. 159:381–389.

 PubMed Web of Science ®Google Scholar

Chen CL, Chiou HY, Hsu LI, Hsueh YM, Wu MM, Wang YH, Chen CJ. 2010a. Arsenic in drinking water and risk of urinary tract cancer: a follow-up study from northeastern Taiwan. Cancer Epidemiol Biomarkers Prev. 19:101–110.

 PubMed Web of Science ®Google Scholar

Ferreccio C, Smith AH, Duran V, Barlaro T, Benitez H, Valdes R, Aguirre JJ, Moore LE, Acevedo J, Vasquez MI, et al. 2013. Case-control study of arsenic in drinking water and kidney cancer in uniquely exposed Northern Chile. Am J Epidemiol. 178:813–818.

 PubMed Web of Science ®Google Scholar

Steinmaus CM, Ferreccio C, Romo JA, Yuan Y, Cortes S, Marshall G, Moore LE, Balmes JR, Liaw J, Golden T, Smith AH. 2013. Drinking water arsenic in northern chile: high cancer risks 40 years after exposure cessation. Cancer Epidemiol Biomarkers Prev. 22:623–630.

 PubMed Web of Science ®Google Scholar

Karagas MR, Tosteson TD, Morris JS, Demidenko E, Mott LA, Heaney J, Schned A. 2004. Incidence of transitional cell carcinoma of the bladder and arsenic exposure in New Hampshire. Cancer Causes Control. 15:465–472.

 PubMed Web of Science ®Google Scholar

Kurttio P, Pukkala E, Kahelin H, Auvinen A, Pekkanen J. 1999. Arsenic concentrations in well water and risk of bladder and kidney cancer in Finland. Environ Health Perspect. 107:705–710.

 PubMed Web of Science ®Google Scholar

Lewis DR, Southwick JW, Ouellet-Hellstrom R, Rench J, Calderon RL. 1999. Drinking water arsenic in Utah: a cohort mortality study. Environ Health Perspect. 107:359–365.

 PubMed Web of Science ®Google Scholar

Meliker JR, Slotnick MJ, Avruskin GA, Schottenfeld D, Jacquez GM, Wilson ML, Goovaerts P, Franzblau A, Nriagu JO. 2010. Lifetime exposure to arsenic in drinking water and bladder cancer: a population-based case-control study in Michigan, USA. Cancer Causes Control. 21:745–757.

 PubMed Web of Science ®Google Scholar

Michaud DS, Wright ME, Cantor KP, Taylor PR, Virtamo J, Albanes D. 2004. Arsenic concentrations in prediagnostic toenails and the risk of bladder cancer in a cohort study of male smokers. Am J Epidemiol. 160:853–859.

 PubMed Web of Science ®Google Scholar

Mostafa MG, Cherry N. 2015. Arsenic in drinking water, transitional cell cancer and chronic cystitis in rural Bangladesh. Int J Enviorn Res Public Health. 12:13739–13749.

 PubMed Web of Science ®Google Scholar

Steinmaus C, Yuan Y, Bates MN, Smith AH. 2003. Case-control study of bladder cancer and drinking water arsenic in the western United States. Am J Epidemiol.Epidemiol. 158:1193–1201.

 PubMed Web of Science ®Google Scholar

Chen CL, Chiou HY, Hsu LI, Hsueh YM, Wu MM, Wang YH, Chen CJ. 2010b. Ingested arsenic, characteristics of well water consumption and risk of different histological types of lung cancer in northeastern Taiwan. Environ Res. 110:455–462.

 PubMed Web of Science ®Google Scholar

Dauphine DC, Smith AH, Yuan Y, Balmes JR, Bates MN, Steinmaus C. 2013. Case-control study of arsenic in drinking water and lung cancer in california and nevada. Ijerph. 10:3310–3324.

 Google Scholar

D’Ippoliti D, Santelli E, De Sario M, Scortichini M, Davoli M, Michelozzi P. 2015. Arsenic in drinking water and mortality for cancer and chronic diseases in central Italy, 1990-2010. PLoS One. 10:e0138182.

 PubMed Web of Science ®Google Scholar

Mostafa MG, McDonald JC, Cherry NM. 2008. Lung cancer and exposure to arsenic in rural Bangladesh. Occup Environ Med. 65:765–768.

 PubMed Web of Science ®Google Scholar

Smith AH, Ercumen A, Yuan Y, Steinmaus CM. 2009. Increased lung cancer risks are similar whether arsenic is ingested or inhaled. J Expo Sci Environ Epidemiol. 19:343–348.

 PubMed Web of Science ®Google Scholar

Chiou HY, Hsueh YM, Liaw KF, Horng SF, Chiang MH, Pu YS, Lin JS, Huang CH, Chen CJ. 1995. Incidence of internal cancers and ingested inorganic arsenic: a seven-year follow-up study in Taiwan. Cancer Res. 55:1296–1300.

 PubMed Web of Science ®Google Scholar

Huang YK, Huang YL, Hsueh YM, Yang MH, Wu MM, Chen SY, Hsu LI, Chen CJ. 2008. Arsenic exposure, urinary arsenic speciation, and the incidence of urothelial carcinoma: a twelve-year follow-up study. Cancer Causes Control. 19:829–839.

 PubMed Web of Science ®Google Scholar

Wang YH, Yeh SD, Shen KH, Shen CH, Juang GD, Hsu LI, Chiou HY, Chen CJ. 2009. A significantly joint effect between arsenic and occupational exposures and risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2 on risk of urothelial carcinoma. Toxicol Appl Pharmacol. 241:111–118.

 PubMed Web of Science ®Google Scholar

Karagas MR, Tosteson TD, Blum J, Klaue B, Weiss JE, Stannard V, Spate V, Morris JS. 2000. Measurement of low levels of arsenic exposure: a comparison of water and toenail concentrations. Am J Epidemiol. 152:84–90.

 PubMed Web of Science ®Google Scholar

Steinmaus C, Ferreccio C, Yuan Y, Acevedo J, González F, Perez L, Cortés S, Balmes JR, Liaw J, Smith AH. 2014. Elevated lung cancer in younger adults and low concentrations of arsenic in water. Am J Epidemiol. 180:1082–1087.

 PubMed Web of Science ®Google Scholar

Koutros S, Baris D, Waddell R, Beane Freeman LE, Colt JS, Schwenn M, Johnson A, Ward MH, Hosain GM, Moore LE, et al. 2018. Potential effect modifiers of the arsenic-bladder cancer risk relationship. Int J Cancer. 143:2640–2646.

 PubMed Web of Science ®Google Scholar

Steinmaus C, Bates MN, Yuan Y, Kalman D, Atallah R, Rey OA, Biggs ML, Hopenhayn C, Moore LE, Hoang BK, Smith AH. 2006. Arsenic methylation and bladder cancer risk in case-control studies in Argentina and the United States. J Occup Environ Med. 48:278–488.

 Web of Science ®Google Scholar

Heck JE, Andrew AS, Onega T, Rigas JR, Jackson BP, Karagas MR, Duell EJ. 2009. Lung cancer in a U.S. population with low to moderate arsenic exposure. Environ Health Perspect. 117:1718–1723.

 PubMed Web of Science ®Google Scholar