Cadmium Exposure in General Populations in Japan: a Review

Abstract

Cadmium (Cd) intake via diet (Cd-D) has been a long-standing focus of administrative as well as public concern in Japan after the endemic of Itai-itai disease (chronic cadmium poisoning). The aim of this report was to review cadmium exposure in Japan by introducing publications from our study group and related articles. Literature survey disclosed that Cd-D was high (up to 100 µg/day) in 1960s even in non-polluted areas. Such high Cd-D levels were followed by gradual decreases in 1970s-1980s to current level of well below 20 µg/day. Once, a very high Cd-D (600 µg/day) was reported for a Cd-polluted area. Replacement of Cd-polluted rice paddy soil with clean soil resulted in substantial reduction in rice-associated Cd-D. In large-scale surveys in 10 prefectures all over Japan conducted early in 2000s, the geometric mean (GM) of Cd-U_cr (Cd in urine as corrected for creatinine concentration) was 1.26 µg/g cr, but was higher in one north-west sea coast prefecture in Honshu Island (>3 µg/g cr). Supplemental survey in 6 neighboring prefectures on the sea coast disclosed that Cd-U_cr in some prefectures were higher as compared with the national average. It was reported that Cd in brown rice was also high. However no clear-cut indication was detected to suggest renal tubular dysfunctions. Surveys in major cities in East and South-East Asia in 1980s-1990s made it clear that Cd-D was substantially lower there than in Japanese cities; Cd exposure of general populations was almost exclusively from foods. Statistical analysis revealed that tubular dysfunction markers increased sharply when Cd-U_cr exceeded 10–12 µg/g cr. The Cd-U_cr level of 11 µg/g cr corresponded to Cd-D level of 59 µg/day. This level was in agreement with the tolerable weekly intake of 7 µg/kg body weight/week, the value recommended by the Food Safety Commission of Japan.

Figures

Fig. 1.

Location of survey sites

[A] Survey sites for the first survey and the second survey. The number in the figure indicates location of each survey sites. Sites for the two surveys were essentially the same. (Cited from Watanabe et al²⁰⁾ and Ikeda et al²¹⁾).

[B] Open circles for locations of survey sites for the large-scale survey in 10 prefectures, and solid circles for the sites for the supplemental survey in the 6 sea-coast prefectures (a solid circle is given also to Pref. No. 15 to show that the prefecture was evaluated also together with other 6 prefectures with solid circles). The number shows the number given by the administration to each prefecture. Note that Pref. No. 15 was surveyed in the former survey, and the data were evaluated also in combination with the 6 prefectures because of its sea-coast location (Revised from Ezaki et al¹³⁾; Yamagami et al⁴⁰⁾, Moriguchi et al⁴¹⁾ and Ikeda et al⁴²⁾).

Fig. 2.

Correlation of Cd in blood (Cd-B) and Cd-in urine (as corrected for creatinine concentration; Cd-U_cr) with dietary Cd intake (Cd-D). Each dot represents one survey site. The line in the middle is the calculated regression line and two dotted curves on both sides show the 95% variation range. For equations, see Table 4. [A] Relation of Cd-B with Cd-D. [B] Relation of Cd-U_cr with Cd-D. (Cited from Ikeda et al²⁵⁾)

Fig. 3.

Variation in the seven neighboring coastal prefectures of natural abundance in Cd. GM values are dotted. Prefectures (from left to right) are Pref. No. 2, Pref. No. 5, Pref. No. 6, Pref. No. 15, Pref. No. 16, Pref. No. 17 and Pref. No. 18. For locations in the map, see Fig. 1 [B]. The line in the middle of each figure shows the national GM. The lines above and below show one GSD range.

[A] Cd in brown rice (Cd-BrR), [B] Cd-U_cr, [C] α₁-MG-U_cr, [D] β₂-MG-U_cr and [E] NAG-U_cr. (Re-prepared from Ikeda et al⁴²⁾)

Fig. 4.

Survey sites in East and South-East Asia. Each dot shows the location of the survey site together with the city name. (Cited from Ikeda et al⁴³⁾)

Fig. 5.

Dose response relationship of α₁-MG with Cd-U, that of β₂-MG with Cd-U.

[A] β2-MG with Cd-U in women. Each symbol represents a GM value for a study group: solid circles for Itai-itai disease patients, solid triangles for chronic Cd poisoning-suspected patients, solid rhomboids for residents in polluted areas, and open circles for residents in non-polluted areas. Solid and broken regression lines are for the groups with >400 and >1000 β2-MG-U/g cr, respectively. For equations, see Table 9. (Cited from Ikeda et al⁴⁵)).

[B] β2-MG with Cd-U in men. Legends are as for Fig. 5 [A].

[C] α1-MG with Cd-U. Each dot represents GM values for a group. For regression line equations, see Table 9. (Cited from Moriguchi et al⁴⁷))

Fig. 6.

Smoking dose-dependent increase in Cd-U. Note that the vertical axis shows the increase in Cd-U as observed (Cd-U_ob) over the levels for non-smokers. The level (GM) for non-smokers were about 1.26 µg/g cr or 1.26 µg/L (Ezaki et al¹³⁾). Δ stands for the increment over the level for non-smokers. (Cited from Ikeda et al⁵¹⁾).

Tables

Table 1.Cd contents in locally consumed polished rice

Area	Cd in polished rice (μg/kg)
	1986a	1996a
Australia	9.07	2.7
China (Continent)	7.58	15.5
China (Taiwan)	74.7	39.6
Colombia	-	133.2
France	-	17.4
Hong Kong	28.2	-
India	9.6	-
Indonesia	20.7	21.8
Italy	42.5	33.9
Japan	52.5	55.7
Korea	16.1	15.7
Malaysia	36.1	27.5
Nepal	21.2	-
Pakistan	11.1	-
Philippines	20.7	20.1
Singapore	11.5	-
South Africa	-	15.8
Thailand	13.6	15
United States	11.5	7.4

GM values are shown. ^a The year of publication; N = 5-29 and 5-218 per area in the 1986 and 1996 publications, respectively. (Cited from Watanabe et al^16,17))

Table 2.Reduction in Cd-D and Cd-B for adult women; comparison in 19 survey sites

Survey	Parameter (GM)
	Cd-D(μg/day)	Cd-B(μg/L)
The first survey	38.0	3.58
The second survey	30.0	1.98

The number of cases was 283 for Cd-D and 484 for Cd-B in the first survey, and 375 for Cd-D and 467 for Cd-B in the second survey. (Cited from Watanabe et al²²⁾)

Table 3.Significant correlation among Cd in food, blood, and urine

	Cd in blood			Cd in urine (non-corrected)			Cd in urine (corrected for creatinine)
	Individual	Site	Region	Individual	Site	Region	Individual	Site	Region
No. of cases	607	30	7	607	30	7	607	30	7
Cd in food	0.4 **	0.7 **	0. 7 o	0.3 **	0.7 **	0. 7 o	0.3 **	0.7 **	0. 6
Cd in blood				0.4 **	0.5 **	0. 8 o	0.6 **	0.8 **	0.9 **
Cd in urine (non-corrected)							0.6 **	0.8 **	0.9 **

**, *, o and ns for P < 0.01, <0.05, <0.10 and ≥0.10, respectively.

(Cited from Shimbo et al²³⁾)

Table 4.Equations for regression lines and confidence ranges

X	Y	Typea	Equation	r ( P )
Cd-B (μg/L)	Cd-D (μg/day)	95% UL	Y = +10.18 + 7.19X + 1.772X2	r = 0.76b (P < 0.001)
		RL	Y = −1.13 + 14.36X
		95% LL	Y = −12.43 + 21.54X − 1.772X2
Cd-Ucr (μg/g cr)	Cd-D (μg/day)	95% UL	Y = +12.84 + 3.33X + 0.169X2	r = 0.79b (P < 0.001)
		RL	Y = +5.35 + 4.90X
		95% LL	Y = −2.13 + 6.48X − 0.169X2

^a The equations are regression line (RL) and 95% upper (95% UL) or lower limit (95% LL). ^b n = 30. (Cited from Ikeda et al²⁵⁾)

Table 5.Annual trend in dietary Cd intake: Comparison between polluted areas and control areas in Japan

Survey year	Methoda	Dietary Cd intake (GM in μg/day)								Reference
		Polluted area				Non-pollued area
		Areab	No.c	Cd-D	Riced	Areab	No.c	Cd-D	Riced
1968	MB	Jinzu		600e						Environ. Agency27); Kitamura28)
1968	MB	Sasu-Shiine		490e		Controls		60e		Environ. Agency27); Kitamura28)
1968	MB	Namari-Nishihasama		320e						Environ. Agency27); Kitamura28)
1968	MB	Usui-Yanase		400e						Environ. Agency27); Kitamura28)
1968	MB							47e		Fukushima29)
1969	FD	Usui-Yanase	3	273f	36	Controls	3	116M	71	Japan Public Health Association30) (Re-calculated from)
1969	FD	Usui-Yanase	3	234g			3	81W		Japan Public Health Association30) (Re-calculated from)
1969	FD	Sasu-Shiine	3	146f	62	Controls	3	96M	46	Japan Public Health Association30) (Re-calculated from)
1969	FD	Sasu-Shiine	3	189g			3	94W		Japan Public Health Association30) (Re-calculated from)
1969	FD	Okutaki	3	224f	32	Controls	3	55M	14	Japan Public Health Association30) (Re-calculated from)
1969	FD	Okutaki	3	358g			3	55W		Japan Public Health Association30) (Re-calculated from)
1969	FD	Namari-Nishihasama				Controls	6	85?	51	Japan Public Health Association30) (Re-calculated from)
1969	??	Sasu-Shiine	587	108h	62					Saito et al33) (assumedly AMg)
1972	FD					28 sites		24?		Yamagata and Iwashima31) (re-caculated from)
1976	FD	Sasu-Shiine	10	206h	43	Controls	10	50?	16	Saito et al33) (assumedly AMg)
1978	FD	Kosaka town	10	92f	47	Controls	10	64M	28	Tsuchiya and Iwao32) (re-calculated from)
1978	FD	Kosaka town	10	92f	70	Controls	10	39M	40	Tsuchiya and Iwao32) (re-calculated from)
1978	FD	Sasu-Shiine	10	128f	49	Controls	10	61M	40	Tsuchiya and Iwao32) (re-calculated from)
1977–1981	FD					22 sites	368	44M	37	Watanabe et al20)
1977–1981	FD					41 sites	674	37W	37	Watanabe et al20)
1983	FD	Sasu-Shiine	24	79h			6	29	30	Saito et al33) (assumedly AMg)
1991–1997	FD					30 sites	607	25W	40	Ikeda et al21)
1999–2000	FD	Kosaka town	40	55h						Saito et al33) (assumedly AMg)
2003–2011								16.5		Cd-B based estimationf, 25)
2003–2011								11.5		Cd-Ucr based estimationf, 25)

^a MB for the market basket method, and FD for the food duplicate method. ^b Names of river basin, unless otherwise specified. ^c No. of cases studied by the food duplicate method. ^d Account for rice in total dietary Cd intake. ^e Only one value was given. ^f For details of estimation, see the text. ^g AM; arithmetic mean. ^M Values for men. ^W Values for women. ^? Values for subjects of unreported gender. (Revised from Ikeda et al²⁶⁾)

Table 6.Cd-U_cr, α₁-MG-U_cr and β₂-MG-U_cr in 10 Prefectures in Japan

Pref. No.	No. of cases	Cd-Ucr(μg/g cr)	α1-MG-Ucr(mg/g cr)	β2-MG-Ucr(μg/g cr)
1	927	1.22	2.48	103
4	1042	1.40	2.72	121
14	1028	1.40	2.08	116
15	994	3.16	3.02	129
20	1323	0.98	2.51	114
26	1213	1.48	3.03	120
34	1131	1.11	2.22	121
39	1104	0.96	2.79	102
40	998	1.16	2.61	109
47	993	0.76	2.05	114
Sum	10,753	1.26	2.54	115

(Cited from Ezaki et al¹³⁾)

Table 7.Dietary Cd intake for adult non-smoking women in large cities in East and South-East Asia in 1990s

Area	City	No.a	Cd-Db
South-East Asia	Bangkok · Kuala Lumpur · Manila · Tainan	195	7.0–14.1
Chinese Continent	Beijing · Shanghai · Jinan · Xian (Nanningc)	250	4.9–9.8 (21.2c)
Japan	Tokyo · Kyoto	61	32.0
Korea	Seoul · Pusan	55	20.9
Total		561	11.3

^a Number of cases studied. ^b GM values (in μg/day) are shown. ^c A possibility of local pollution due to mining was considered.

(Cited from Ikeda et al⁴³⁾)

Table 8.Oral and respiratory uptake of cadmium

City	Route	Conc. in air (ng/m3)	Intake (μg/day)	Uptake (ng/day)	Total (ng/day)	Oral/Total (%)
Japan: Tokyo + Kyoto	Oral	-	34.5	2588b	2602	99.5%
	Respiratory	0.5–6.7	0.054a	13.7c
Malaysia: Kuala Lumpur	Oral	-	7.1	533b	538	99.0%
	Respiratory	0.28–1.85	0.016a	5.4c

^a Respiration volume: 15 m³/day. ^b Absorption in the G-I tract: 5%–10%. ^c Absorption in the lung: 50%. (Cited from Ikeda et al⁴³⁾)

Table 9.Regression analysis for threshold value

Parameter	Sex	Group		No. of groups	Intercept	Slope	r	Xc
α1-MG	Men+Women	Non-exposed		3	2.156	0.281	0.57d
		Exposed		10	−1476.762	127	0.92e	11.6
β2-MG	Women	Non-exposed		30	176	−25	0.35f
		Exposed	Total	29
			Aa	25	−68313	6194	0.65e	11.0
			Bb	19	−77606	6642	0.60e	11.7
	Men	Non-exposed		17	274	−82	0.60e
		Exposed	Total	16
			Aa	12	−64016	6243	0.91e	10.0
			Bb	10	−79371	7155	0.94e	11.0

^a Cases with β₂-MG >400 µg/g cr. ^b Cases with β₂-MG >1000 µg/g cr. ^c X (Cd-U_cr) for the point to meet; unit for X; μg/g cr. ^dP > 0.10. ^eP < 0.01. ^f 0.05 < P < 0.10. (Cited from Ikeda et al⁴⁵⁾ and Moriguchi et al⁴⁷⁾)

Table 10.Benchmark dose calculated taking α₁-MG-U_cr, β₂-MG-U_cr or NAG-U_cr as effect parameter

Item	Tubular function parameter
	α1-MG-Ucr	β2-MG-Ucr	NAG-Ucr
No.a	16	16	9c
Median	1.46	1.65	1.47
Minimum	0.78	0.82	0.70
Maximum	2.51	3.00	4.98
Max./Min.b	3.22	3.66	7.11

^a Number of prefectures surveyed. ^b Maximum/Minimum. ^c BMD for NAG could not be calculated for technical reasons (for details, see Section 11). (Cited from Sakuragi et al⁴⁸⁾)

Table 11.Multiple regression analysis to detect effect of Cd-U on BMD and BMDL

Dependent variable: BMD for	Independent variables						R2	r	P for r
	Age		Creatinine		Cd-U
	SRCa	P	SRCa	P	SRCa	P
α1-MG-Ucr	0.33	*	0.27	ns	0.56	*	0.74	0.86	**
β2-MG-Ucr	0.1	ns	0.39	ns	0.55	*	0.76	0.87	**
NAG-Ucr	0.01	ns	0.93	**	0.09	ns	0.93	0.96	**

** for P < 0.01: * for P < 0.05; ns for P ≥ 0.05. ^a SRC: Standardized regression coefficient. (Cited from Sakuragi et al⁴⁸⁾)

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