Our results show that increasing arsenic...

Our results show that increasing arsenic intake from drinking water was associated with bladder cancer risk only when comparing patients with p16+ or Rb+ tumors with controls (representing 72.8% and 74.0% of tumors, respectively), with a strong monotonic association with increasing intake (compared with lowest unlagged exposure, OR_p16+ = 1.36, 95% CI = 1.47 to 1.85, P_trend = .004; OR_Rb+ = 1.51, 95% CI = 1.56 to 1.94, P_trend = .007) (Table 1). There was no association between arsenic and p16- or Rb- bladder tumors (P_{heterogeneity} by subtype = .03 for p16 and .06 for Rb). This heterogeneity was not evident across subtypes defined by stage or grade (Supplementary Table 1, available online) despite the relationship of these markers with stage and grade of bladder cancer (4).

Cumulative arsenic quartiles	Case negative	Case positive	Control	Immunophenotype* OR (95% CI)†	P_{heterogeneity}‡
Unlagged, mg
0–15.70	29	53	327	Ref	Ref
>15.70–34.50	31	74	321	1.03 (0.59 to 1.79)	1.36 (0.91 to 2.03)
>34.50–77.04	27	80	321	0.88 (0.50 to 1.55)	1.47 (0.99 to 2.19)
>77.04	28	102	318	0.88 (0.50 to 1.56)	1.85 (1.25 to 2.72)	.03
P_trend§				.60	.005
Lagged–40 y, mg
0–3.52	33	56	313	Ref	Ref
>3.52–8.77	28	69	308	0.80 (0.46 to 1.41)	1.18 (0.78 to 1.77)
>8.77–22.42	20	73	311	0.61 (0.33 to 1.15)	1.43 (0.95 to 2.16)
>22.42	32	107	305	0.98 (0.55 to 1.75)	2.12 (1.39 to 3.22)	.06
P_trend§				.75	<.001
Unlagged, mg				Rb IHC (-)	Rb IHC (+)
0–15.70	29	46	327	Ref	Ref
>15.70–34.50	23	72	321	0.79 (0.44 to 1.42)	1.51 (1.00 to 2.30)
>34.50–77.04	18	76	321	0.60 (0.32 to 1.13)	1.56 (1.03 to 2.37)
>77.04	30	93	318	0.95 (0.54 to 1.67)	1.94 (1.29 to 2.92)	.19
P_trend§				.78	.007
Lagged–40 y, mg
0–3.52	25	56	313	Ref	Ref
>3.52–8.77	24	63	308	0.95 (0.51 to 1.76)	1.13 (0.74 to 1.73)
>8.77–22.42	23	64	311	0.93 (0.49 to 1.77)	1.24 (0.80 to 1.92)
>22.42	27	101	305	1.03 (0.54 to 1.95)	2.00 (1.30 to 3.05)	.06
P_trend§				.83	<.001

Cumulative arsenic quartiles	Case negative	Case positive	Control	Immunophenotype* OR (95% CI)†	P_{heterogeneity}‡
Unlagged, mg
0–15.70	29	53	327	Ref	Ref
>15.70–34.50	31	74	321	1.03 (0.59 to 1.79)	1.36 (0.91 to 2.03)
>34.50–77.04	27	80	321	0.88 (0.50 to 1.55)	1.47 (0.99 to 2.19)
>77.04	28	102	318	0.88 (0.50 to 1.56)	1.85 (1.25 to 2.72)	.03
P_trend§				.60	.005
Lagged–40 y, mg
0–3.52	33	56	313	Ref	Ref
>3.52–8.77	28	69	308	0.80 (0.46 to 1.41)	1.18 (0.78 to 1.77)
>8.77–22.42	20	73	311	0.61 (0.33 to 1.15)	1.43 (0.95 to 2.16)
>22.42	32	107	305	0.98 (0.55 to 1.75)	2.12 (1.39 to 3.22)	.06
P_trend§				.75	<.001
Unlagged, mg				Rb IHC (-)	Rb IHC (+)
0–15.70	29	46	327	Ref	Ref
>15.70–34.50	23	72	321	0.79 (0.44 to 1.42)	1.51 (1.00 to 2.30)
>34.50–77.04	18	76	321	0.60 (0.32 to 1.13)	1.56 (1.03 to 2.37)
>77.04	30	93	318	0.95 (0.54 to 1.67)	1.94 (1.29 to 2.92)	.19
P_trend§				.78	.007
Lagged–40 y, mg
0–3.52	25	56	313	Ref	Ref
>3.52–8.77	24	63	308	0.95 (0.51 to 1.76)	1.13 (0.74 to 1.73)
>8.77–22.42	23	64	311	0.93 (0.49 to 1.77)	1.24 (0.80 to 1.92)
>22.42	27	101	305	1.03 (0.54 to 1.95)	2.00 (1.30 to 3.05)	.06
P_trend§				.83	<.001

Table 1.

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Association between cumulative arsenic exposure and bladder cancer risk by tumor immunophenotype

Cumulative arsenic quartiles	Case negative	Case positive	Control	Immunophenotype* OR (95% CI)†		P_{heterogeneity}‡
				p16 IHC (-)	p16 IHC (+)
Unlagged, mg
0–15.70	29	53	327	Ref	Ref
>15.70–34.50	31	74	321	1.03 (0.59 to 1.79)	1.36 (0.91 to 2.03)
>34.50–77.04	27	80	321	0.88 (0.50 to 1.55)	1.47 (0.99 to 2.19)
>77.04	28	102	318	0.88 (0.50 to 1.56)	1.85 (1.25 to 2.72)	.03
P_trend§				.60	.005
Lagged–40 y, mg
0–3.52	33	56	313	Ref	Ref
>3.52–8.77	28	69	308	0.80 (0.46 to 1.41)	1.18 (0.78 to 1.77)
>8.77–22.42	20	73	311	0.61 (0.33 to 1.15)	1.43 (0.95 to 2.16)
>22.42	32	107	305	0.98 (0.55 to 1.75)	2.12 (1.39 to 3.22)	.06
P_trend§				.75	<.001
Unlagged, mg				Rb IHC (-)	Rb IHC (+)
0–15.70	29	46	327	Ref	Ref
>15.70–34.50	23	72	321	0.79 (0.44 to 1.42)	1.51 (1.00 to 2.30)
>34.50–77.04	18	76	321	0.60 (0.32 to 1.13)	1.56 (1.03 to 2.37)
>77.04	30	93	318	0.95 (0.54 to 1.67)	1.94 (1.29 to 2.92)	.19
P_trend§				.78	.007
Lagged–40 y, mg
0–3.52	25	56	313	Ref	Ref
>3.52–8.77	24	63	308	0.95 (0.51 to 1.76)	1.13 (0.74 to 1.73)
>8.77–22.42	23	64	311	0.93 (0.49 to 1.77)	1.24 (0.80 to 1.92)
>22.42	27	101	305	1.03 (0.54 to 1.95)	2.00 (1.30 to 3.05)	.06
P_trend§				.83	<.001

Cumulative arsenic quartiles	Case negative	Case positive	Control	Immunophenotype* OR (95% CI)†		P_{heterogeneity}‡
				p16 IHC (-)	p16 IHC (+)
Unlagged, mg
0–15.70	29	53	327	Ref	Ref
>15.70–34.50	31	74	321	1.03 (0.59 to 1.79)	1.36 (0.91 to 2.03)
>34.50–77.04	27	80	321	0.88 (0.50 to 1.55)	1.47 (0.99 to 2.19)
>77.04	28	102	318	0.88 (0.50 to 1.56)	1.85 (1.25 to 2.72)	.03
P_trend§				.60	.005
Lagged–40 y, mg
0–3.52	33	56	313	Ref	Ref
>3.52–8.77	28	69	308	0.80 (0.46 to 1.41)	1.18 (0.78 to 1.77)
>8.77–22.42	20	73	311	0.61 (0.33 to 1.15)	1.43 (0.95 to 2.16)
>22.42	32	107	305	0.98 (0.55 to 1.75)	2.12 (1.39 to 3.22)	.06
P_trend§				.75	<.001
Unlagged, mg				Rb IHC (-)	Rb IHC (+)
0–15.70	29	46	327	Ref	Ref
>15.70–34.50	23	72	321	0.79 (0.44 to 1.42)	1.51 (1.00 to 2.30)
>34.50–77.04	18	76	321	0.60 (0.32 to 1.13)	1.56 (1.03 to 2.37)
>77.04	30	93	318	0.95 (0.54 to 1.67)	1.94 (1.29 to 2.92)	.19
P_trend§				.78	.007
Lagged–40 y, mg
0–3.52	25	56	313	Ref	Ref
>3.52–8.77	24	63	308	0.95 (0.51 to 1.76)	1.13 (0.74 to 1.73)
>8.77–22.42	23	64	311	0.93 (0.49 to 1.77)	1.24 (0.80 to 1.92)
>22.42	27	101	305	1.03 (0.54 to 1.95)	2.00 (1.30 to 3.05)	.06
P_trend§				.83	<.001

Cutoff values used to define negative and positive staining for each marker were based on the distribution of the percentage of positive cells among all cases (30% for both markers). Spearman correlation among markers was .24 (P < .05, two-sided P value computed using t distribution with n = 2 degrees of freedom). CI = confidence interval; HR = hazard ratio; IHC = immunohistochemistry.

†

Odds ratios and 95% confidence intervals from polytomous logistic regression are adjusted for age, sex, ethnicity, smoking, disinfection by products, and high-risk occupation.

‡

P_{heterogeneity} based on a two-sided Wald test.

P_trend based on a two-sided Wald test for linear trend.

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