Summary prepared by Ted Schettler, M.D., MPH, Science Director for the Science and Environmental Health Network. He is also associated with Physicians for Social Responsibility, Greater Boston Chapter.

Notes:

1 Rier SE, Martin DC, Bowman RE, et. al. Endometriosis in Rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fund Appl Toxicol 21:433-441, 1993.

2 Pluim JJ, deVilder J, Olie K, et. al. Effects of pre- and postnatal exposure to chlorinated dioxins and furans on human neonatal thyroid concentrations. Environ Health Perspect 101:504-508, 1993.

3 Nessel CS, Gallo MA. Dioxins and related compounds. In: Environmental Toxicants, Ed. Lippmann M. Van Nostrand Reinhold, New York, 1992.

4 Sweeney MH, Hornung RW, Wall DK, et.al. Prevalence of diabetes and elevated serum glucose levels in workers exposed to 2,3,7,8-tetrachloro-p-dioxin. Organohalogens 11:225-226, 1992.

5 Carcinogenicity of TCDD in animals. Draft dioxin reassessment. EPA/600/AP-92/001f, 1992.

6 Huff J. Dioxins and mammalian carcinogenesis. In: Schecter A. ed. Dioxins and health. New York: Plenum Press, 1994.

7 Hardell L, Sandstrom A. Case-control study.: Soft-tissue sarcomas and exposure to phenoxyacetic acids or chlorophenols. Br J Cancer 39:711-717, 1979.

8 Erikkson M, Hardell L, Berg NO, et. al. Soft-tissue sarcomas and exposure to chemical substances: A case-referent study. Br J Ind Med 38: 27-33, 1981.

9 Hardell L, Erikkson M, Lenner P, et. al. Malignant lymphoma and exposure to chemicals, especially organic solvents, chlorophenols, and phenoxy acids: a case-control study. Br J Cancer 43: 169-176 1981.

10 Hardell L, Johansson B, Axelson O. Epidemiological study of nasal and nasopharyngeal cancer and their relation to phenoxy acid or chlorophenol exposure. Am J Ind Med 3: 247-257, 1982.

11 Fingerhut MA, Halperin WE, Marlow DA, et. al. Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N Engl J Med 324:212-218, 1991.

12 Smith AH, Fisher DO, Giles HJ, et. al. The New Zealand soft tissue sarcoma case-control study: Interview findings concerning phenoxyacetic acid exposure. Chemosphere12:565-571.

13 Kang HK, Weatherbee L, Breslin PP, et.al. Soft tissue sarcomas and military service in Vietnam: A case comparison group analysis of hospital patients. J Occup Med 28: 1215-1218, 1986.

14 Thigpen JE, Faith RE, McConnell EE, Moore JA. Increased susceptibility to bacterial infection as a sequela of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Infect Immun 12:1319-1324.

15 House RV, Lauer RD, Murray MJ, et.al. Examination of immune parameters and host resistance mechanisms in B6C3F1 mice following adult exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Toxicol Envi on Health 31:203-215, 1990.

16 Tucker AN, Vore SJ, Luster MI. Suppression of B cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Mol Pharmacol 29:372-377, 1986.

17 Luster MI, Boorman GA, Dean JH. Examination of bone marrow, immunologic parameters, and host susceptibility following pre- and post-natal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). nt J Immunopharmacol 2:301-310, 1980.

18 Murray FJ, Smith FA, Nitschke GG, et.al. Three-generation reproduction study of rats give 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the diet. Toxicol Appl Pharmacol 50:241-252, 1979.

19 Allen JR, Barsotti DA, Lambrecht LK, et. al. Reproductive effects of halogenated aromatic hydrocarbons on non-human primates. Ann NY Acad Sci 320:419-425, 1979.

20 Kociba RJ, Keeler PA, Park GN, et. al. 2,3,7,8-tetrachlorodibenzo-p-dioxin: Results of a 13-week oral toxicity study in rats. Toxicol Appl Pharmacol 35:553-574, 1976.

21 Schantz SL, Bowman RE. Learning in monkeys exposed perinatally to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Neurotox Teratol 11:13-19, 1989.

22 Mably TA, Moore RW, Peterson RE. In utero and lactational exposure of male rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin: 1. Effects on androgenic status. Toxicol Appl Pharmacol 114:97-107, 1992.

23 Egeland GM, Sweney MH, Fingerhut MA, et. al. Total serum testosterone and gonadotropins in workers exposed to dioxin. Am J Epidemiol 139(3):272-281, 1994.

24 Erickson JD, Mulinare J, McClain PW, et. al. Vietnam veterans' risks for fathering babies with birth defects. JAMA 252:903-912, 1984

25 Wolfe WH, Michalek JE, Miner JC, et. al. Paternal serum dioxin and reproductive outcomes among veterans of Operation Ranch Hand. Epidemiology 6(1):17-22, 1995.

Dr. Schettler notes that this summary is not exhaustive.

The health effects of dioxin have been extensively studied in animals and to a lesser extent, in humans. Binding of a dioxin molecule to a cellular receptor seems to be necessary for expression of biochemical and toxic effects, though some investigators question whether this is how dioxin interferes with the immune system. The dioxin-receptor combination is further processed and transported to the nucleus of a cell where it binds to DNA, interfering with the normal expression of genes. Observed effects include stimulation of enzyme production and alteration of production and metabolism of various hormones, growth factors, and other naturally-occurring chemicals.

Dioxin causes cancer in laboratory animals, and several studies of humans show an increased incidence of various forms of cancer. It is also toxic to the immune system and interferes with normal reproduction and development. Primate studies show an association between dioxin exposure and endometriosis.1 Dioxin interferes with thyroid hormone levels in infants.2 These effects may occur at extremely low exposure levels. Large accidental or occupational exposures cause a skin rash (chloracne), weight loss, fatigue, decreased libido, altered glucose metabolism, and neurological damage.3 4 In animals studies, susceptibility to the various forms of toxicity varies considerably among species. Species variability is less marked, however, among fetuses and infants, with some health effects detectable after extremely low exposures even in species whose adults are relatively resistant. There is also evidence of considerable variability of susceptibility among individuals.

Cancer

Dioxin repeatedly causes cancer in virtually all studies in experimental animals at doses well below those which are otherwise toxic.5 Carcinogenesis is a multi-stage process. Though dioxin does not appear to initiate the events leading to cancer, it behaves as a potent cancer promoter - i.e., once the initial events have occurred, dioxin triggers others necessary for a malignant tumor to appear. It modifies hormones involved in cell growth and differentiation. This undoubtedly explains how dioxin exposure causes an increased incidence of many different types of tumors. Experimental animals exposed to very low doses of dioxin under varying circumstances may develop cancers of different organs, including the liver, adrenal gland, thyroid , skin, lung, nose, and palate.6

Studies of cancer in humans exposed to dioxin have produced mixed results. Some show increased incidence of soft-tissue sarcoma 7 8, non-Hodgkin's lymphoma 9, and nasal cancer 10. A particularly comprehensive study of workers from 12 different industrial facilities showed increased mortality from soft-tissue sarcomas and all cancers among those exposed to dioxin.11 Others have not found similar increases.12 13 Dioxin is classified as a known human carcinogen by the International Agency for Research on Cancer (IARC), and probable human carcinogen by the Environmental Protection Agency (EPA).

Immune system toxicity

Effects on antibody response and other forms of immune-system expression have been extensively studied and documented. Effects on the immune system of the developing organism appear to be among the most sensitive endpoints studied. Extraordinarily low single doses in pregnant animals cause lifelong changes in the immune system of offspring. In experimental animal studies, dioxin exposures of far less than one microgram/kg cause a decreased immune response and increased susceptibility to viral, bacterial, and parasitic infections.14 15 16 Prenatal exposure to dioxin at low levels causes increased growth of transplanted tumor cells in offspring.17 This may well represent immune-system toxicity since the immune system plays an important role in cancer surveillance and suppression.

A number of studies in humans exposed to dioxin have shown effects on various measurements of the immune system in blood tests. The importance of these changes is not clear. More research is needed to determine if these changes are correlated with increased susceptibility to infection or more severe disease.

Reproductive and developmental toxicity

Animal studies show that dioxin exposure is associated with decreased fertility and litter size and inability to carry pregnancies to term.18 19 Offspring have lowered testosterone levels, decreased sperm counts, birth defects, and learning disabilities. 20 21 Many of these effects are seen at very low exposure levels, demonstrating the exquisite sensitivity of the developing fetus to dioxin. In one rat study, a single low maternal dose of dioxin (0.16 micrograms/kg) on day 15 of pregnancy reduced male testosterone levels, delayed descent of the testicles, made the genital area more female-like, and reduced sperm production and prostate weight in male offspring.22 It also demasculinized their behavior in months that follow. These results have been replicated in many different laboratories.

Human studies have shown lowered testosterone levels in exposed workers and birth defects in offspring of Vietnam veterans exposed to Agent Orange, an herbicide containing dioxin.23 24 25

In the U.S., a breast-feeding infant is exposed to approximately 50-60 picogram dioxin (TEQ)/kg/day, a level considerably higher than average adult exposure levels of approximately 3 picograms/kg/day. Nursing infant exposures are at levels which cause abnormalities in animal studies. All studies of dioxin toxicity indicate that early development is the lifestage of greatest sensitivity to many of its health effects. However, since many of the adverse effects of fetal or infant dioxin exposure may be apparent only much later in life, human epidemiological studies of the results of those exposures have yet to be conducted since early exposures are impossible to estimate with accuracy.