How Does Contamination of Rice Soils with Cd and Zn Cause High Incidence of Human Cd Disease in Subsistence Rice Farmers

Current Pollution Reports

Volumn 1, Issue 1, 2015, Pages 13-22

  Chaney, Rufus L ^a  

^a AGRICULTURAL RESEARCH SERVICE   (United States)

Author keywords

Cadmium; Chelator buffered; Flooded; Manganese; NRAMP5; Oryza sativa; Translocation; Zinc; ZNT1

Indexed keywords

EID: 84945256991     PISSN: None     EISSN: 21986592     Source Type: Journal    
DOI: 10.1007/s40726-015-0002-4     Document Type: Review

References (111)

1. Kobayashi J. Pollution by cadmium and the itai-itai disease in Japan. In: Oehme FW, editor. Toxicity of heavy metals in the environment. New York: Marcel Dekker, Inc; 1978. p. l99–260
2. Nogawa K, Kobayashi E, Okubo Y, Suwazono Y. Environmental cadmium exposure, adverse effects and preventive measures in Japan. BioMetals. 2004;17:581–7
3. Horiguchi H, Aoshima K, Oguma E, Sasaki S, Miyamoto K, Hosoi Y, et al. Latest status of cadmium accumulation and its effects on kidneys, bone, and erythropoiesis in inhabitants of the formerly cadmium-polluted Jinzu River Basin in Toyama, Japan, after restoration of rice paddies. Int Arch Occup Environ Health. 2010;83:953–70
4. Tsuchiya K. Cadmium studies in Japan: a review. New York: Elsevier/North-Holland Biomedical Press; 1978
5. Asami T. Pollution of soils by cadmium. In: Nriagu JO, editor. Changing metal cycles and human health. Berlin: Springer-Verlag; 1984. p. 95–111
6. Cai S, Yue L, Hu Z, Zhong X, Ye Z, Xu H, et al. Cadmium exposure and health effects among residents in an irrigation area with ore dressing wastewater. Sci Total Environ. 1990;90:67–73
7. Jin T, Nordberg G, Ye T, Bo M, Wang H, Zhu G, et al. Osteoporosis and renal dysfunction in a general population exposed to cadmium in China. Environ Res. 2004;96:353–9
8. Swaddiwudhipong W, Limpatanachote P, Mahasakpan P, Krintratun S, Padungtod C. Cadmium-exposed population in Mae Sot District, Tak Province: 1. Prevalence of high urinary cadmium levels in the adults. J Med Assoc Thail. 2007;90:143–8
9. Chaney RL, Ryan JA, Li Y-M, Brown SL. Soil cadmium as a threat to human health. In: McLaughlin MJ, Singh BR, editors. Cadmium in soils and plants. Dordrecht: Kluwer Academic Publ.; 1999. p. 219–56
10. Chaney RL, Ryan JA, Reeves PG. Cadmium in soils and its transfer to plants and the human food chain. In: Proc. Eighth International Cadmium Conference (Nov. 10–13, 2011, Kunming, China). Brussels, Belgium: International Cadmium Association; 2013. pp. 175–212
11. Grant CA, Clarke JM, Duguid M, Chaney RL. Selection and breeding of plant cultivars to minimize cadmium accumulation. Sci Total Environ. 2008;390:301–10
12. Chaney RL. Cadmium and zinc (Chapter 17). In: Hooda P, editor. Trace elements in soils. Oxford: Blackwell Publ.; 2010. p. 409–39
13. Chaney RL. Zinc phytotoxicity. In: Robson AD, editor. Proceedings of the international symposium on zinc in soils and plants. Dordrecht: Kluwer Academic Publisher; 1993. p. 135–50
14. Chaney RL, Ryan JA. Risk based standards for arsenic, lead and cadmium in urban soils. (ISBN 3-926959-63-0). Frankfurt: DECHEMA; 1994
15. Ewers U, Freier I, Turfeld M, Brockhaus A, Hofstetter I, König W, et al. Heavy metals in garden soil and vegetables from private gardens located in lead/zinc smelter area and exposure of gardeners to lead and cadmium (in German). Gesundheitswesen. 1993;55:318–25
16. Sarasua SM, McGeehin MA, Stallings FL, Terracciano GJ, Amler RW, Logue JN, et al. Final Report. Technical Assistance to the Pennsylvania Department of Health. Biologic indicators of exposure to cadmium and lead. Palmerton: Part II. Atlants, GA: Agency for Toxic Substances and Disease Registry, US-DHHS; 1995. p. 1–57
17. Strehlow CD, Barltrop D. The Shipham report – An investigation into cadmium concentrations and its implications for human health: 6. Health studies. Sci Total Environ. 1988;75:101–33
18. Sharma RP, Kjellström T, McKenzie JM. Cadmium in blood and urine among smokers and non-smokers with high cadmium intake via food. Toxicology. 1983;29:163–71
19. Vahter M, Berglund M, Nermell B, Åkesson A. Bioavailability of cadmium from shellfish and mixed diet in women. Toxicol Appl Pharmacol. 1996;136:332–41
20. Sirot V, Samieri C, Volatier J-L, LeBlanc J-C. Cadmium dietary intake and biomarker data in French high seafood consumers. J Expo Sci Environ Epidemiol. 2008;28:400–9
21. Chaney RL, Stoewsand GS, Bache CA, Lisk DJ. Cadmium deposition and hepatic microsomal induction in mice fed lettuce grown on municipal sludge-amended soil. J Agric Food Chem. 1978;26:992–4
22. Chaney RL, Stoewsand GS, Furr AK, Bache CA, Lisk DJ. Elemental content of tissues of Guinea pigs fed Swiss chard grown on municipal sewage sludge-amended soil. J Agric Food Chem. 1978;26:944–97
23. McKenna IM, Chaney RL, Tao SH, Leach Jr RM, Williams FM. Interactions of plant zinc and plant species on the bioavailability of plant cadmium to Japanese quail fed lettuce and spinach. Environ Res. 1992;57:73–87
24. 115mcadmium in Japanese quail produced by a combined supplement of zinc copper and manganese. J Nutr. 1978;108:901–10
25. Fox MRS, Jacobs RM, Jones AOL, Fry Jr BE. Effects of nutritional factors on metabolism of dietary cadmium at levels similar to those of man. Environ Health Perspect. 1979;28:107–14
26. Takijima Y, Katsumi F, Takezawa K. Cadmium contamination of soils and rice plants caused by zinc mining: 2. Soil conditions of contaminated paddy fields which influence heavy metal contents in rice. Soil Sci Plant Nutr. 1973;19:173–82
27. Takijima Y, Katsumi F, Koizumi S. Cadmium contamination of soils and rice plants caused by zinc mining. 3. Effects of water management and applied organic manures on the control of Cd uptake by plants. Soil Sci Plant Nutr. 1973;19:183–93
28. Iimura K. Chemical forms and behavior of heavy metals in soils. In: Kitagishi K, Yamane I, editors. Heavy metal pollution in soils of Japan. Tokyo: Japan Scientific Societies Press; 1981. p. 27–36
29. Chino M. Uptake-transport of toxic metals in rice plants. In: Kitagishi K, Yamane I, editors. Heavy metal pollution in soils of Japan. Tokyo: Scientific Societies Press; 1981. p. 81–94
30. Chino M. The assessment of various countermeasures against Cd pollution in rice grains. In: Kitagishi K, Yamane I, editors. Heavy metal pollution in soils of Japan. Tokyo: Scientific Societies Press; 1981. p. 281–5
31. Fukushima M, Ishizaki A, Sakamoto M, Kobayashi E. Cadmium concentration in rice eaten by farmers in the Jinzu River basin (in Japanese). Jpn J Hyg. 1973;28:406–15
32. Simmons RW, Pongsakul P, Chaney RL, Saiyasitpanich D, Klinphoklap S, Nobuntou W. The relative exclusion of zinc and iron from rice grain in relation to rice grain cadmium as compared to soybean: Implications for human health. Plant Soil. 2003;257:163–70
33. Hattori H, Asari E, Chino M. Estimate of cadmium concentration in brown rice. Bangkok: 17th World Congress of Soil Science; 2002. p. 1992–1–5
34. Ito H, Iimura K. Absorption of cadmium by rice plants in response to change of oxidation-reduction conditions of soils (in Japanese). J Sci Soil Manure Jpn. 1975;46:82–8
35. Khaokaew S, Chaney RL, Landrot G, Ginder-Vogel M, Sparks DL. Speciation and release kinetics of cadmium in an alkaline paddy soil under various flooding periods and draining conditions. Environ Sci Technol. 2011;45:4249–55
36. de Livera J, McLaughlin MJ, Hettiarachchi GM, Kirby JK, Beak DG. Cadmium solubility in paddy soils: effects of soil oxidation, metal sulfides and competitive ions. Sci Total Environ. 2011;409:1489–97
37. Fulda B, Voegelin A, Kretzschmar R. Redox-controlled changes in cadmium solubility and solid-phase speciation in a paddy soil as affected by reducible sulfate and copper. Environ Sci Technol. 2013;47:12775–83
38. de Livera J, McLaughlin MJ, Beak D, Hettiarachchi GM, Kirby J. Release of dissolved cadmium and sulfur nanoparticles from oxidizing sulfide minerals. Soil Sci Soc Am J. 2011;75:842–54
39. Saito H, Shioji R, Hurukawa Y, Nagai K, Arikawa T, Saito T, et al. Cadmium-induced proximal tubular dysfunction in a cadmium-polluted area. Contrib Nephrol. 1977;6:1–12
40. Arao T, Kawasaki A, Baba K, Mori S, Matsumoto S. Effect of water management on cadmium and arsenic accumulation and dimethylarsinic acid concentrations in Japanese rice. Environ Sci Technol. 2009;43:9361–7
41. Kawasaki A, Arao T, Ishikawa S. Reducing cadmium content of rice grains by means of flooding and a few problems. Jpn J Hyg. 2012;67:478–83
42. Murakami M, Nakagawa F, Ae N, Ito N, Arao T. Phytoextraction by rice capable of accumulating Cd at high levels: reduction of Cd content of rice grain. Environ Sci Technol. 2009;43:5878–83
43. Chino M, Baba A. The effects of some environmental factors on the partitioning of zinc and cadmium between roots and tops of rice plants. J Plant Nutr. 1981;3:203–14
44. Simmons RW, Noble AD, Pongsakul P, Sukreeyapongse O, Chinabut N. Analysis of field-moist Cd contaminated paddy soils during rice grain fill allows reliable prediction of grain Cd levels. Plant Soil. 2008;302:125–37
45. Yu H, Wang J, Yuan J, Yang Z, Fang W. Cadmium accumulation in different rice cultivars and screening for pollution-safe cultivars of rice. Sci Total Environ. 2006;370:302–9
46. Ueno D, Koyama E, Yamaji N, Ma JF. Physiological, genetic, and molecular characterization of a high-Cd-accumulating rice cultivar. Jarjan J Exp Bot. 2011;62:2265–72
47. Arao T, Ishikawa S, Murakami M, Abe K, Maejima Y, Makino T. Heavy metal contamination of agricultural soil and countermeasures in Japan. Paddy Water Environ. 2010;8:247–57
48. Chino M. The distribution of heavy metals in rice plants influenced by the time and the path of supply (in Japanese). J Sci Soil Manure Jpn. 1973;44:204–10
49. Rodda MS, Li G, Reid RJ. The timing of grain Cd accumulation in rice plants: the relative importance of remobilisation within the plant and root Cd uptake post-flowering. Plant Soil. 2011;347:105–14
50. Yamaguchi N, Ishikawa S, Abe T, Baba K, Arao T, Terada Y. Role of the node in controlling traffic of cadmium, zinc, and manganese in rice. J Exp Bot. 2012;63:2729–37
51. Fujimaki S, Suzui N, Ishioka NS, Kawachi N, Ito S, Chino M, et al. Tracing cadmium from culture to spikelet: noninvasive imaging and quantitative characterization of absorption, transport, and accumulation of cadmium in an intact rice plant. Plant Physiol. 2010;152:1796–806
52. Ishikawa S, Ishimaru Y, Igura M, Kuramata M, Abe T, Senoura T, et al. Ion-beam irradiation, gene identification, and marker-assisted breeding in the development of low-cadmium rice. Proc Natl Acad Sci U S A. 2012;109:19166–71
53. Ishimaru Y, Takahashi R, Bashir K, Shimo H, Senoura T, Sugimoto K, et al. Characterizing the role of rice NRAMP5 in manganese, iron and cadmium transport. Sci Rep. 2012;2:286
54. Sasaki A, Yamaji N, Yokosho K, Ma JF. Nramp5 is a major transporter responsible for manganese and cadmium uptake in rice. Plant Cell. 2012;24:2155–67
55. Yang M, Zhang Y, Zhang L, Hu J, Zhang X, Lu K, et al. OsNRAMP5 contributes to manganese translocation and distribution in rice shoots. J Exp Bot. 2014;65:4849–61
56. Hart JJ, Welch RM, Norvell WA, Kochian LV. Transport interactions between cadmium and zinc in roots of bread and durum wheat seedlings. Physiol Plant. 2002;116:73–8
57. Hart JJ, Welch RM, Norvell WA, Clarke JM, Kochian LV. Zinc effects on cadmium accumulation and partitioning in near-isogenic lines of durum wheat that differ in grain cadmium concentration. New Phytol. 2005;167:391–401
58. McKenna IM, Chaney RL, Williams FM. The effects of cadmium and zinc interactions on the accumulation and tissue distribution of zinc and cadmium in lettuce and spinach. Environ Pollut. 1993;79:113–20
59. Chaney RL, Li Y-M, Schneiter AA, Green CE, Miller JF, Hopkins DG. Progress in developing technologies to produce low Cd concentration sunflower kernels. In: Proceedings of the 15th sunflower research workshop. Fargo: National Sunflower Association; 1993. p. 80–92
60. Cohen CK, Fox TC, Garvin DF, Kochian LV. The role of iron-deficiency stress responses in stimulating heavy-metal transport in plants. Plant Physiol. 1998;116:1063–72
61. Cohen CK, Garvin DF, Kochian LV. Kinetic properties of a micronutrient transporter from Pisum sativum indicate a primary function in Fe uptake from the soil. Planta. 2004;218:784–92
62. Meng F, Liu D, Yang X, Shohag MJ, Yang J, Li T, et al. Zinc uptake kinetics in the low and high-affinity systems of two contrasting rice genotypes. J Plant Nutr Soil Sci. 2014;177:412–20
63. Hacisalihoglu G, Hart JJ, Kochian LV. High- and low-affinity zinc transport systems and their possible role in zinc efficiency in bread wheat. Plant Physiol. 2001;125:456–63
64. Kukier U, Chaney RL. Growing rice grain with controlled Cd concentrations. J Plant Nutr. 2002;25:1793–820
65. Ramesh SA, Shin R, Eide DJ, Schachtman DP. Differential metal selectivity and gene expression of two zinc transporters from rice. Plant Physiol. 2003;133:126–34
66. Yang X, Huang J, Jiang Y, Zhang H-S. Cloning and functional identification of two members of the ZIP (Zrt, Irt-like protein) gene family in rice (Oryza sativa L.). Mol Biol Rep. 2009;36:281–7
67. Chen WR, Feng Y, Chao YE. Genomic analysis and expression pattern of OsZIP1, OsZIP3, and OsZIP4 in two rice (Oryza sativa L.) genotypes with different zinc efficiency. Russ J Plant Physiol. 2008;55:400–9
68. Bashir K, Ishimaru Y, Nishizawa NK. Molecular mechanisms of zinc uptake and translocation in rice. Plant Soil. 2012;361:189–201
69. Bouis HE, Welch RM. Biofortification – A sustainable agricultural strategy for reducing micronutrient malnutrition in the global south. Crop Sci. 2010;50:S20–32
70. Cakmak I. Enrichment of cereal grains with zinc: agronomic or genetic biofortification? Plant Soil. 2008;302:1–17
71. Phattarakul N, Rerkasem B, Li LJ, Wu LH, Zou CQ, Zhang FS, et al. Biofortification of rice grain with zinc through zinc fertilization in different countries. Plant Soil. 2012;361:131–41
72. 65Zn after flowering in aerobic rice. Ann Appl Biol. 2007;150:383–91
73. Boonchuay P, Cakmak I, Rerkasem B, Prom-U-Thai C. Effect of different foliar zinc application at different growth stages on seed zinc concentration and its impact on seedling vigor in rice. Soil Sci Plant Nutr. 2013;59:180–8
74. Stomph TJ, Jiang W, Struik PC. Zinc biofortification of cereals: rice differs from wheat and barley. Trends Plant Sci. 2009;12:123–4
75. Yoshikawa T, Kusaka S, Zikihara T, Yoshida T. Distribution of heavy metals in rice plants. I. Distribution of heavy metal elements in rice grains using an electron probe x-ray microanalyser (EPMA). J Soc Soil Manure Jpn. 1977;48:523–8. In Japanese
76. Jiang W, Struik PC, van Keulen H, Zhao M, Jin LN, Stomph TJ. Does increased zinc uptake enhance grain zinc mass concentration in rice? Ann Appl Biol. 2008;153:135–47
77. Gao X, Hoffland E, Stomph T, Grant CA, Zou C, Zhang F. Improving zinc bioavailability in transition from flooded to aerobic rice. A review. Agron Sustain Dev. 2012;32:465–78
78. Gao X, Zou C, Fan X, Zhang FS, Hoffland E. From flooded to aerobic conditions in rice cultivation: consequences for zinc uptake. Plant Soil. 2006;280:41–7
79. Chaney RL, Anders MM, McClung A. Effect of Irrigation Water Management on As and Cd in Rice Grain. In Abstracts/Proceedings for International Plant Nutrition Colloquium, Istanbul, Turkey; 2013. pp. 182–83
80. Brown SL, Angle JS, Chaney RL. Correction of limed-biosolid induced manganese deficiency on a long-term field experiment. J Environ Qual. 1997;26:1375–84
81. Ma JF, Yamaji N, Mitani N, Xu X-Y, Su Y-H, McGrath SP, et al. Transporters of arsenite in rice and their role in arsenic accumulation in rice grain. Proc Natl Acad Sci U S A. 2008;105:9931–5
82. Linquist BA, Anders M, Adviento-Borbe MA, Chaney RL, Nalley LL, da Rosa E, et al. Reducing greenhouse gas emissions, water use and grain arsenic levels in rice systems. Glob Chang Biol. 2015;21:407–17
83. 1B-type of ATPase affects root-to-shoot cadmium translocation in rice by mediating efflux into vacuoles. New Phytol. 2011;189:190–9
84. Ueno D, Yamaji N, Kono I, Huang CF, Ando T, Yano M, et al. Gene limiting cadmium accumulation in rice. Proc Natl Acad Sci U S A. 2010;107:16500–5
85. Benitez ER, Hajika M, TakahashI R. Single-base substitution in P1B-ATPase gene is associated with a major QTL for seed cadmium concentration in soybean. J Hered. 2012;103:278–86
86. Ibaraki T, Fujitomi S-I, Ishitsuka A, Yanaka M. Phytoextraction by high-Cd-accumulating rice to reduce Cd in wheat grains grown in Cd-polluted fields. Soil Sci Plant Nutr. 2014;60:266–75
87. Takahashi R, Ishimaru Y, Shimo H, Ogo Y, Senoura T, Nishizawa NK, et al. The OsHMA2 transporter is involved in root-to-shoot translocation of Zn and Cd in rice. Plant Cell Environ. 2012;35:1948–57
88. Satoh-Nagasawa N, Mori M, Nakazawa N, Kawamoto T, Nagato Y, Sakurai K, et al. Mutations in rice (Oryza sativa) heavy metal ATPase 2 (OsHMA2) restrict the translocation of zinc and cadmium. Plant Cell Physiol. 2012;53:213–24
89. Uraguchi S, Kamiya T, Sakamoto T, Kasai K, Sato Y, Nagamura Y, et al. Low-affinity cation transporter (OsLCT1) regulates cadmium transport into rice grains. Proc Natl Acad Sci U S A. 2011;108:20959–64
90. Oliver DP, Hannam R, Tiller KG, Wilhelm N, Merry RH. The effects of zinc fertilization on cadmium concentration in wheat grain. J Environ Qual. 1994;23:705–11
91. Chaney RL, Filcheva E, Green CE, Brown SL. Zn deficiency promotes Cd accumulation by lettuce from biosolids amended soils with high Cd:Zn ratio. J Resid Sci Technol. 2006;3:68–75
92. Mench MJ, Martin E, Solda P. After effects of metals derived from a highly metal-polluted sludge on maize (Zea mays L.). Water Air Soil Pollut. 1994;75:277–91
93. Fox MRS. Nutritional factors that may influence bioavailability of cadmium. J Environ Qual. 1988;17:175–80
94. Flanagan PR, McLellan JS, Haist J, Cherian G, Chamberlain MJ, Valberg LS. Increased dietary cadmium absorption in mice and human subjects with iron deficiency. Gastroenterology. 1978;74:841–6
95. Park JD, Cherrington NJ, Klaassen CD. Intestinal absorption of cadmium is associated with divalent metal transporter 1 in rats. Toxicol Sci. 2002;68:288–94
96. Ryu D-Y, Lee S-J, Park DW, Choi B-S, Klaassen CD, Park J-D. Dietary iron regulates intestinal cadmium absorption through iron transporters in rats. Toxicol Lett. 2004;152:19–25
97. Reeves PG, Chaney RL. Bioavailability as an issue in risk assessment and management of food cadmium: a review. Sci Total Environ. 2008;398:13–9
98. Reeves PG, Chaney RL. Mineral nutrient status of female rats affects the absorption and organ distribution of cadmium from sunflower kernels (Helianthus annuus L.). Environ Res. 2001;85:215–25
99. Reeves PG, Chaney RL. Marginal nutritional status of zinc, iron, and calcium increases cadmium retention in the duodenum and other organs of rats fed a rice-based diet. Environ Res. 2004;96:311–22
100. Reeves PG, Chaney RL, Simmons RW, Cherian MG. Metallothionein induction is not involved in cadmium accumulation in the duodenum of mice and rats fed diets containing high-cadmium-rice or sunflower kernels and a marginal supply of zinc, iron, and calcium. J Nutr. 2005;135:99–108
101. JECFA. Evaluation of certain food additives and contaminants. Sixty-first Report of the Joint FAO/WHO Expert Committee on Food Additives. 2003. WHO Technical Report Series 922. http://whqlibdoc.who.int/trs/WHO_TRS_922.pdf
102. EFSA (European Food Safety Agency). Scientific Opinion of the Panel on Contaminants in the Food Chain on a request from the European Commission on cadmium in food. EFSA J. 2009; 980:1–139. http://www.efsa.europa.eu/en/efsajournal/doc/980.pdf
103. JECFA. Joint FAO/WHO Expert Committee on Food Additives, Summary Report on the 73rd meeting, (Geneva, 8–18 June, 2010). 2010. http://www.who.int/foodsafety/publications/chem/summary73.pdf
104. EFSA (European Food Safety Agency). Statement on Tolerable Weekly Intake of Cadmium. EFSA J. 2011; 9(2):1975. http://www.efsa.europa.eu/en/efsajournal/doc/1975.pdf
105. Reeves PG, Nielsen EJ, O’Brien-Nimens C, Vanderpool RA. Cadmium bioavailability from edible sunflower kernels: a long-term study with men and women volunteers. Environ Res. 2001;A87:81–91
106. Buhler DR. Availability of cadmium from foods and water. In: Calabrese EJ, Tuthill RW, Condie L, editors. Inorganics in drinking water and cardiovascular disease. Princton: Princeton Scientific Publ. Co.; 1987. p. 271–87
107. Chaney RL, Green CE, Ajwa H, Smith R. Zinc fertilization plus liming to reduce cadmium uptake by Romaine lettuce on Cd-mineralized Lockwood soil. Proc. Int. Plant Nutrition Colloquium XVI (Aug. 25–28, 2009, Sacramento, CA): 2009. Paper 1252. (http://repositories.cdlib.org/ipnc/xvi/1252)
108. 2-microglobulin among general Japanese populations. Toxicol Lett. 2003;137:135–41
109. Ezaki T, Tsukahara T, Moriguchi J, Furuki K, Fukui Y, Ukai H, et al. No clear-cut evidence for cadmium-induced renal tubular dysfunction among over 10,000 women in the Japanese general population: a nationwide large-scale survey. Int Arch Occup Environ Health. 2003;76:186–96
110. Ikeda M, Ezaki T, Moriguchi J, Fukui Y, Okamoto S, Ukai H, et al. No meaningful increase in urinary tubular dysfunction markers in a population with 3 μg cadmium/g creatinine in urine. Biol Trace Elem Res. 2006;113:35–44
111. Tohyama C, Shaikh ZA, Nogawa K, Kobayashi E, Honda R. Elevated urinary excretion of metallothionein due to environmental cadmium exposure. Toxicology. 1981;20:289–97