Assessment of risks to human health from chemical agents is a complex process that requires the assembly, careful analysis, and integration of human and animal data collected from studies performed at different times, for disparate purposes, and under varying conditions. The application of risk assessment methods to data without consideration of the relevance of critical experimental parameters such as route of exposure or magnitude of dose can lead to specious determinations of the risk posed by exposure to environmental agents. A case study of the purported risk of developmental toxicity from inorganic arsenic is presented to illustrate (1) the nature of the problem, (2) how extant data from all studies are useful, (3) how appropriately designed modern studies can clarify the situation, and (4) how conflicted data should be evaluated in terms of appropriateness for use in risk assessment.
Ancel, P.1946–1947. Recherche expérimental sur le spina bifida. Arch. Anat. Microsc. Morphol. Exp.36:45–68.
2.
Ancel, P., and S. Lallemand. 1941. Sur l'arrêt de développement du bourgeon caudal obtenu expérimentalement chez l'embryon de poulet. Arch. Physique Biol.15:27–29.
3.
Aposhian, H. V.1997. Enzymatic methylation of arsenic species and other new approaches to arsenic toxicity. Annu. Rev. Pharmacol. Toxicol.37:397–419.
4.
Aschengrau, A., S. Zierler, and A. Cohen. 1989. Quality of community drinking water and the occurrence of spontaneous abortion. Arch. Environ. Health44:283–290.
5.
Baxley, M. N., R. D. Hood, G. C. Vedel, W. P. Harrison, and G. M. Szczech. 1981. Prenatal toxicity of orally administered sodium arsenite in mice. Bull. Environ. Contam. Toxicol.26:749–756.
6.
Beaudoin, A. R.1974. Teratogenicity of sodium arsenate in rats. Teratology10:153–158.
7.
Beckman, L., and S. Nordström. 1982. Occupational and environmental risks in and around a smelter in northern Sweden. IX. Fetal mortality among wives of smelter workers. Hereditas97:1–7.
8.
Birge, W. J., and O. W. Roberts. 1976. Toxicity of metals to chick embyros. Bull. Environ. Contam. Toxicol.16:319–324.
9.
Börzsönyi, M., A. Bereczky, P. Rudnai, M. Csanady, and A. Horvath. 1992. Epidemiological studies on human subjects exposed to arsenic in drinking water in southeast Hungary [letter]. Arch. Toxicol.66:77–78.
10.
Boyle, R. W., and I. R. Jonasson. 1973. The geochemistry of arsenic and its use as an indicator element in geochemical prospecting. J. Geochem. Explor.2:251–296.
11.
Burk, D., and A. R. Beaudoin. 1977. Arsenate-induced renal agenesis in rats. Teratology16:247–260.
12.
Carpenter, S. J.1987. Developmental analysis of cephalic axial dysraphic disorders in arsenic-treated hamster embryos. Anat. Embryol.176:345–366.
13.
Chaineau, E., S. Binet, D. Pol, G. Chatellier, and V. Meininger. 1990. Embryotoxic effects of sodium arsenite and sodium arsenate on mouse embryos in culture. Teratology41:105–112.
14.
Chappell, W. R., and J. Mordenti. 1991. Extrapolation of toxicological and pharmacological data from animals to humans. Adv. Drug Res.20:1–116.
15.
Davidson, I. W. F., J. C. Parker, and R. P. Beliles. 1986. Biological basis for extrapolation across mammalian species. Regul. Toxicol. Pharmacol.6:211–237.
16.
DeSesso, J. M., C. F. Jacobson, A. R. Scialli, C. H. Farr, and J. F. Holson. 1998. An assessment of the developmental toxicity of inorganic arsenic. Reprod. Toxicol.12:385–433.
17.
Ducoff, H. S., W. B. Neal, R. L. Straube, L. O. Jacobson, and A. M. Brues. 1948. Biological studies with arsenic76. II. Excretion and tissue localization. Proc. Soc. Exp. Biol. Med.69:548–554.
18.
Ferm, V. H., and S. J. Carpenter. 1968. Malformations induced by sodium arsenate. J. Reprod. Fertil.17:199–201.
19.
Ferm, V. H., A. Saxon, and B. M. Smith. 1971. The teratogenic profile of sodium arsenate in the golden hamster. Arch. Environ. Health22:557–560.
20.
Gilani, S. H., and Y. Alibhai. 1990. Teratogenicity of metals to chick embryos. J. Toxicol. Environ. Health30:23–31.
21.
Hanlon, D. P., and V. H. Ferm. 1986. Concentration and chemical status of arsenic in the blood of pregnant hamsters during critical embryogenesis. 2. Acute exposure, Environ. Res.40:380–390.
22.
Harris, S. B., and J. M. DeSesso. 1994. Practical guidance for evaluating and interpreting developmental toxicity tests. J. Hazardous Materials39:245–266.
23.
Holmberg, R. E. Jr., and V. H. Ferm. 1969. Interrelationships of selenium, cadmium, and arsenic in mammalian teratogenesis. Arch. Environ. Health18:873–877.
24.
Holson, J. F. D. G. Stump, K. J. Clevidence, J. F. Knapp, and C. H. Farr. In press. a. Evaluation of the prenatal developmental toxicity of orally administered arsenic trioxide in rats. Food Chem. Toxicol.
25.
Holson, J. F. D. G. Stump, C. E. Ulrich, and C. H. Farr. In press. b. Absence of prenatal developmental toxicity from inhaled arsenic trioxide in rats. Toxicol. Sci.
26.
Hood, R. D.1972. Effects of sodium arsenite on fetal development. Bull. Environ. Contam. Toxicol.7:216–222.
27.
Hood, R. D., and S. L. Bishop. 1972. Teratogenic effects of sodium arsenate in mice. Arch. Environ. Health24:62–65.
28.
Hood, R. D., and W. P. Harrison. 1982. Effects of prenatal arsenite exposure in the hamster. Bull. Environ. Contam. Toxicol.29:671–678.
29.
Hood, R. D., and C. T. Pike. 1972. BAL alleviation of arsenate-induced teratogenesis in mice. Teratology6:235–238.
30.
Hood, R. D., G. T. Thacker, and B. L. Patterson. 1977. Effects in the mouse and rat of prenatal exposure to arsenic. Environ. Health Perspect.19:219–222.
31.
Hood, R. D., G. T. Thacker, B. L. Patterson, and G. M. Szczech. 1978. Prenatal effects of oral versus intraperitoneal sodium arsenate in mice. J. Environ Pathol. Toxicol.1:857–864.
32.
Hood, R. D., and G. C. Vedel-Macrander. 1984. Evaluation of the effect of BAL (2,3-dimercaptopropanol) on arsenite-induced teratogenesis in mice. Toxicol. Appl. Pharmacol.73:1–7.
33.
Hood, R. D., G. C. Vedel-Macrander, M. J. Zaworotko, F. M. Tatum, and R. G. Meeks. 1987. Distribution, metabolism, and fetal uptake of pentavalent arsenic in pregnant mice following oral or intraperitoneal administration. Teratology35:19–25.
34.
Hood, R. D., G. C. Vedel, M. J. Zaworotko, F. M. Tatum, and R. G. Meeks. 1988. Uptake, distribution, and metabolism of trivalent arsenic in the pregnant mouse. J. Toxicol. Environ. Health25:423–434.
35.
Hunter, F. T., A. F. Kip, and J. W. Irvine. 1942. Radioactive tracer studies on arsenic injected as potassium arsenite. J. Pharmacol. Exp. Therapeutics76:207–220.
36.
Ihrig, M. M.1997. Effect of chronic inhalation of inorganic arsenic on the risk of stillbirth in a community surrounding an agriculture chemical production facility: A hospital-based study. Masters thesis, Texas A & M University.
37.
Ihrig, M. M., S. L. Shalat, and C. Baynes. 1998. A hospital-based case-control study of stillbirths and environmental exposure to arsenic using an atmospheric dispersion model linked to a geographical information system. Epidemiology9:290–294.
38.
James, L. F., V. A. Lazar, and W. Binns. 1966. Effects of sublethal doses of certain minerals on pregnant ewes and fetal development. Am. J. Vet. Res.27:132–135.
39.
Kojima, H.1974. Studies on developmental pharmacology of arsenic. 2. Effect of arsenite on pregnancy, nutrition and hard tissue. Folia Pharmacol. Japonica70:149–163.
40.
Lanz, H. Jr., P. C. Wallace, and J. G. Hamilton. 1950. The metabolism of arsenic in laboratory animals using As74 as a tracer. Univ. Cal. Pub. Pharmacol.2:263–282.
41.
Marafante, E., F. Bertolero, J. Edel, R. Pietra, and E. Sabbioni. 1982. Intracellular interaction and biotransformation of arsenite in rats and rabbits. Sci. Total Environ.24:27–39.
42.
Mason, R. W., I. R. Edwards, and L. C. Fisher. 1989. Teratogenicity of combinations of sodium dichromate, sodium arsenate and copper sulphate in the rat. Comp. Biochem. Physiol.93C:407–411.
43.
Matsumoto, N., T. Okino, H. Katsunuma, and S. Iijima. 1973. Effects of Na-arsenate on the growth and development of the foetal mice. Teratology8:98.
44.
McKinney, J. D.1992. Metabolism and disposition of inorganic arsenic in laboratory animals and humans. Environ. Geochem. Health14:43–48.
45.
Mirkes, P. E., and L. Cornel. 1992. A comparison of sodium arsenite- and hyperthermia-induced stress responses and abnormal development in cultured postimplantation rat embryos. Teratology46:251–259.
46.
Morrissey, R. E., B. A. Fowler, M. W. Harris, M. P. Moorman, C. W. Jameson, and B. A. Schwetz. 1990. Arsine: Absence of developmental toxicity in rats and mice. Fundam. Appl. Toxicol.15:350–356.
47.
Morrissey, R. E., and N. K. Mottet. 1983. Arsenic-induced exencephaly in the mouse and associated lesions occurring during neurulation. Teratology28:399–411.
48.
Müller, W. U., C. Streffer, and C. Fischer-Lahdo. 1986. Toxicity of sodium arsenite in mouse embryos in vitro and its influence on radiation risk. Arch. Toxicol.59:172–175.
49.
Nagymajtényi, L., A. Selypes, and G. Berencsi. 1985. Chromosomal aberrations and fetotoxic effects of atmospheric arsenic exposure in mice. J. Appl. Toxicol.5:61–63.
50.
Nemec, M. D., J. F. Holson, C. H. Farr, and R. D. Hood. 1998. Developmental toxicity assessment of arsenic acid in mice and rabbits. Reprod. Toxicol.12:647–658.
51.
Nordström, S., L. Beckman, and I. Nordenson. 1978a. Occupational and environmental risks in and around a smelter in northern Sweden. I. Variations in birth weight. Hereditas88:43–46.
52.
Nordström, S., L. Beckman, and I. Nordenson. 1978b. Occupational and environmental risks in and around a smelter in northern Sweden. III. Frequencies of spontaneous abortion. Hereditas88:51–54.
53.
Nordström, S., L. Beckman, and I. Nordenson. 1979a. Occupational and environmental risks in and around a smelter in northern Sweden. V. Spontaneous abortion among female employees and decreased birth weight in their off spring. Hereditas90:291–296.
54.
Nordström, S., L. Beckman, and I. Nordenson. 1979b. Occupational and environmental risks in and around a smelter in northern Sweden. VI. Congenital malformations. Hereditas90:297–302.
55.
Odanaka, Y., O. Matano, and S. Goto. 1980. Biomethylation of inorganic arsenic by the rat and some laboratory animals. Bull. Environ. Contam. Toxicol.24:452–459.
56.
Peterková, R., and L. Puzanová.1976. Effect of trivalent and pentavalent arsenic on early developmental stages of the chick embryo. Folia Morphol.24:5–13.
57.
Rhoads, K., and C. L. Sanders. 1985. Lung clearance, translocation, and acute toxicity of arsenic, beryllium, cadmium, cobalt, lead, selenium, vanadium, and ytterbium oxides following deposition in the rat lung. Environ. Res.36:359–378.
58.
Ridgway, L. P., and D. A. Karnofsky. 1952. The effects of metals on the chick embryo: Toxicity and production of abnormalities in development. Ann. NY Acad. Sci.55:203–215.
59.
Schroeder, H. A., and M. Mitchener. 1971. Toxic effects of trace elements on the reproduction of mice and rats. Arch. Environ. Health23:102–106.
60.
Seidenberg, J. M., D. G. Anderson, and R. A. Becker. 1986. Validation of an in vivo developmental toxicity screen in the mouse. Teratogen. Carcinogen. Mutagen.6:361–374.
61.
Stump, D. G., K. J. Clevidence, J. F. Knapp, J. F. Holson, and C. H. Farr. 1998a. An oral developmental toxicity study of arsenic trioxide in rats. Teratology57:216–217.
62.
Stump, D. G., T. L. Fleeman, M. D. Nemec, J. F. Holson, and C. H. Farr. 1998b. Evaluation of the teratogenicity of sodium arsenate and arsenic trioxide following single oral or intraperitoneal administration in rats. Teratology57:217.
63.
Stump, D. G. J. F. Holson, T. L. Fleeman, M. D. Nemec, and C. H. Farr. In press. Comparative effects of single intraperitoneal or oral doses of sodium arsenate or arsenic trioxide during in utero development. Teratology.
64.
Stump, D. G., C. E. Ulrich, J. F. Holson, and C. H. Farr. 1998c. An inhalation developmental toxicity study of arsenic trioxide in rats. Teratology57:216.
65.
Tabacova, S., D. D. Baird, L. Balabaeva, D. Lolova, and I. Petrov.1994a. Placental arsenic and cadmium in relation to lipid peroxides and glutathione levels in maternal-infant pairs from a copper smelter area. Placenta15:873–881.
66.
Tabacova, S., E. S. Hunter 3rd, and B. C. Gladen. 1996. Developmental toxicity of inorganic arsenic in whole embryo culture: Oxidation state, dose, time, and gestational age dependence. Toxicol. Appl. Pharmacol.138:298–307.
67.
Tabacova, S., R. E. Little, L. Balabaeva, S. Pavlova, and I. Petrov.1994b. Complications of pregnancy in relation to maternal lipid peroxides, glutathione, and exposure to metals. Reprod. Toxicol.8:217–224.
68.
Tamaki, S., and W. T. Frankenberger JR. 1992. Environmental biochemistry of arsenic. Rev. Environ. Contam. Toxicol.124:79–110.
69.
Texas Department of Health. 1992. An investigation of a cluster of neural tube defects in Cameron County, Texas. Report.
70.
Umpierre, C. C.1981. Embryolethal and teratogenic effects of sodium arsenite in rats. Teratology23:66A.
71.
Vahter, M.1994a. Species differences in the metabolism of arsenic compounds. Appl. Organomet. Chem.8:175–182.
72.
Vahter, M.1994b. Species differences in the metabolism of arsenic. In Arsenic exposure and health, ed. W. R. Chappell, C. O. Abernathy, and C. R. Cothern, 171–179. Northwood, England: Science and Technology Letters.
73.
Vahter, M., R. Couch, B. Nermell, and R. Nilsson. 1995. Lack of methylation of inorganic arsenic in the chimpanzee. Toxicol. Appl. Pharmacol.133:262–268.
74.
Vahter, M., and J. Envall. 1983. In vivo reduction of arsenate in mice and rabbits. Environ. Res.32:14–24.
75.
Vahter, M., E. Marafante, A. Lindgren, and L. Dencker. 1982. Tissue distribution and subcellular binding of arsenic in marmoset monkeys after injection of 74As-arsenite. Arch. Toxicol.51:65–77.
Zierler, S., M. Theodore, A. Cohen, and K. J. Rothman. 1988. Chemical quality of maternal drinking water and congenital heart disease. Int. J. Epidemiol.17:589–594.
