Polychlorinated Dibenzodioxins and Polychlorinated Dibenzofurans - PSL1

Toxicology

The compound 2,3,7,8-tetrachlorodibenzodioxin (and to a lesser extent, the other dioxins and furans which are substituted in the 2, 3, 7 and 8 positions) are extremely toxic to mammals, with a wide variation in sensitivity among species. Bird and fish species tested seem to be more sensitive than most mammals to acute exposures to dioxins. In laboratory animals, death results from a single exposure to amounts ranging from less than one microgram to a few milligrams per kilogram of body weight. Longer-term exposure to lesser amounts can activate enzymes or lead to tissue damage. It can also affect reproduction, cause developmental deformities in the fetus and cause cancer. However, 2,3,7,8-tetrachlorodibenzodioxin does not appear to damage the genetic material or chromosomes.

The no-observed-adverse-effect-level for 2,3,7,8- tetrachlorodibenzodioxin for chronic exposure in rats (cancer and reproduction) is approximately 1 nanogram per kilogram of body weight per day.

Dioxins and furans that are not substituted in the 2, 3, 7 or 8 positions are far less toxic and are less capable of inducing enzymes.

Short-term exposure in mammals

Mammals vary widely in their sensitivity to single-dose exposures of dioxins and furans. For 2,3,7,8-tetrachlorodibenzodioxin -- the most acutely toxic of all dioxins and furans -- the lethal oral dose resulting in death for 50 percent of the exposed animals ranges from 0.6 micrograms per kilogram of body weight for guinea pigs to 5051 micrograms per kilogram of body weight for hamsters.³⁵ Recent data on mink show them to be a sensitive species with a median lethal dose of 4.2 micrograms per kilogram.³⁶ Guinea pigs are more sensitive than rats or monkeys, which are in turn more sensitive than rabbits or mice. The common effects on all mammals exposed to 2,3,7,8-tetra-chlorodibenzodioxin are loss of body weight and shrinkage of the thymus gland, followed by death approximately three weeks after exposure. Other effects commonly observed in one or more test mammals include: skin changes, such as eruptions, thickening or discolouration; hair loss; liver damage; and changes in the white cells of the blood and bone marrow.

While other dioxins and furans are less acutely toxic than 2,3,7,8-tetrachloro-dibenzodioxin, they produce similar symptoms. Their toxicity varies widely and depends on the number and position of the chlorine atoms on the molecule. The most toxic dioxins and furans are those with four, five or six chlorines, particularly when substitution is in the 2, 3, 7 and 8 positions.³⁷

Long-term exposure in mammals

Test animals subjected to longer-term oral exposures of 2,3,7,8-tetrachlorodibenzodioxin exhibit many of the symptoms produced by acute exposures.³⁷ Exposed animals display a "wasting syndrome," which includes reduced food consumption and decreased body weight, often followed by death. Several species develop acne-like lesions. Some lose facial hair, and some suffer fluid build-up under the skin or in the body cavity.

Animals exposed to lethal or sublethal doses of 2,3,7,8-tetrachlorodibenzo-dioxin may also exhibit a marked loss of fat; shrinkage of the thymus, spleen and other lymphoid tissues; changes in numbers of blood cells; elevation of several serum enzymes indicative of tissue damage; changes in the liver; and thickening of the gastrointestinal tract, the gall bladder or the bile duct.

Exposure studies of other dioxins and furans substituted in the 2, 3, 7 and 8 positions have shown similar effects. However, higher doses were needed to elicit the same response as a given dose of 2,3,7,8-tetrachlorodibenzodioxin.

Other effects of concern that result from long-term exposure to dioxins and furans must also be considered in the assessment of health risk. For example, most dioxins and furans substituted in the 2, 3, 7 and 8 positions affect the mammalian immune system. ³⁷ Sustained exposures in mammals have led to suppression of both cell-mediated and humoral-mediated immune responses. This is significant because immune suppression compromises the body's ability to fight infection.

Animal studies indicate that long-term exposure to 2,3,7,8-tetrachlorodi-benzodioxin can result in the formation of tumours and carcinomas.^{37 38} Mice exposed orally for a lifetime to 2,3,7,8-tetrachlorodibenzodioxin developed cancer of the liver and thyroid. Rats exposed the same way developed cancer of the liver, lung, tongue, hard palate and nose. Lifetime doses in rats of 0.1 microgram per kilogram of body weight per day resulted in tumours predominantly in the liver, but no increases in liver tumours or nodules were observed in rats or mice at 0.001 microgram per kilogram of body weight per day. Both repeated skin applications and injections of 2,3,7,8- tetrachlorodibenzodioxin have resulted in an increase in malignant tumours in different animal species.

Over the lifetime of rats, oral exposures, to a mixture of hexachloro-dioxins led to an increase in liver cancer.³⁹ However, exposure to 2,7-dichloro-dibenzodioxin did not.

Most studies suggest that 2,3,7,8-tetrachlorodibenzodioxin acts only as a promoter of cancer and not as a complete carcinogen. In addition, the presence of tumours both at, and remote from, the treatment site indicates 2,3,7,8-tetrachlorodibenzodioxin can act both locally and throughout the body.

Despite its ability to promote or cause cancer, 2,3,7,8-tetrachlorodibenzo-dioxin does not appear to affect the genetic material of cells (i.e., it is not genotoxic).³⁹ This is supported by negative findings in a variety of studies on well established mutagenicity test systems. Also, 2,3,7,8- tetrachlorodibenzodioxin does not appear to cause changes in chromosome structure. Together, these data suggest that 2,3,7,8-tetrachlorodibenzodioxin and possibly other dioxins and furans which are substituted in the 2, 3, 7 and 8 positions induce cancer by a non-genetic mechanism, which has implications for the method of estimating risk to humans.

Dioxins and furans can also affect reproduction and the development of offspring depending on the dose, the specific compound involved, the route of administration and the animal species. The reproductive ability of rats exposed to 2,3,7,8-tetrachlorodibenzodioxin was clearly affected in a three-generation study.⁴⁰ Effects on fertility, litter size, fetal resorption and organ function occurred at 0.1 and 0.01 micrograms per kilogram of body weight per day, but not at 0.001 micrograms per kilogram of body weight per day. The reproductive functions of monkeys are quite sensitive to the effects of 2,3,7,8-tetrachlorodibenzodioxin. Spontaneous abortions occurred at 1 microgram per kilogram of body weight per day, but not at 0.2 micrograms per kilogram of body weight per day.⁴¹ Several studies have reported degeneration of the testes and functional impairment in the males of several exposed mammalian species.

Oral administration of 2,3,7,8-tetrachlorodibenzodioxin to pregnant mice has resulted in the development of malformations of the palate and kidney in the fetus.⁴² Other species are less sensitive in this regard than mice. In general, dioxins and furans substituted in the 2, 3, 7 and 8 positions have some potential to produce deformities in mice, while other chlorinated dioxins and furans do not.

Another factor to consider while assessing health risks is that most dioxins and furans substituted in the 2, 3, 7 and 8 positions are potent inducers of enzymes,⁴² including the liver enzymes that play a role in metabolizing foreign substances. The induction of enzymes is not necessarily dangerous, but indicates that the cells have recognized the presence of a foreign substance and have heightened their response readiness. The toxic dioxins and furans are potent inducers of enzymes, whereas the less toxic dioxins and furans are less able to induce this effect.

Fish

Yellow perch, carp, bullhead, rainbow trout, largemouth bass and bluegill have an 80-day lethal dose for 2,3,7,8-tetrachlorodibenzodioxin ranging from 2 to 23 micrograms per kilogram of body weight (centring around 10 micrograms per kilogram of body weight⁴³). At the highest treatment concentration, the time to death varied from 7 days in the perch to 44 days in the carp. The remaining species had a time to death in the range of 16 to 22 days, which is similar to that of mammals. The only common lethal effect between species was the degeneration of the fin tissue. Some species exhibited effects such as weight loss and hyperpigmentation.

Recent data on rainbow trout show effects upon growth, survival and behaviour at water concentrations of less than 38 picograms of 2,3,7,8-tetrachlorodibenzodioxin per litre.⁴⁴ The "no-effect concentration" could not be determined. The mortality curve was time- and concentration-dependent; that is, the longer the time, the lower the concentration that was lethal.

Growth inhibition was dose-dependent, as were behaviourial responses including lethargic swimming, feeding inhibition and lack of response to external stimuli. These effects on fish are in addition to the earlier observations of fluid build-up (edema).⁴⁵

Birds

A recent review has examined the toxicity of 2,3,7,8-tetrachlorodibenzodioxin to birds.⁴⁶ Lethal dose values, computed 37 days after one oral dose of 2,3,7,8-tetrachlorodibenzodioxin, vary from 15 micrograms per kilogram of body weight in the northern bobwhite, to more than 810 micrograms per kilogram of body weight for the ringed turtle-dove. Mallards were intermediate in sensitivity with an acute oral lethal dose value of more than 108 micrograms per kilogram of body weight.⁴⁷ Signs of toxicity began seven days after treatment. For all three species, death was delayed, occurring 13 to 37 days after exposure.

Autopsies of ringed turtle-doves that survived treatment showed livers enlarged to twice the normal size. Bobwhites showed severe emaciation, high accumulations of uric acid salts in connective tissues, and fluid accumulations in the lung, heart and abdominal cavities.⁴⁷

Domestic chickens have an estimated oral lethal dose range of 25 to 50 micrograms of 2,3,7, 8-tetrachlorodibenzodioxin per kilogram of body weight.⁴⁷ Chickens fed lower doses (which were often lethal) showed signs of extensive fluid buildup under the skin and in the body cavity. This is referred to as chick edema disease.⁴⁸ Autopsies of poultry that died following a chlorophenol reactor explosion in Seveso, Italy, in 1976, showed signs characteristic of chick edema disease.⁴⁹ Large amounts of dioxins substituted in the 2, 3, 7 and 8 positions were released at the time of the accident.

³⁵  OME, 1985; WHO, 1989 (in press).

³⁶  Hochstein et al., 1988.

³⁷  OME, 1985; U.S.EPA, 1985; WHO, 1989 (in press).

³⁸  IARC, 1987.

³⁹  OME, 1985; WHO, 1989 (in press).

⁴⁰ Murray et al., 1979.

⁴¹  McNulty et al., 1982.

⁴²  OME, 1985; WHO, 1989 (in press).

⁴³  Kleeman et al., 1988.

⁴⁴  Mehrle et al., 1988.

⁴⁵  Helder, 1980, 1981.

⁴⁶  Eisler, 1986.

⁴⁷ Hudson et al., 1984.

⁴⁸ NRCC, 1981a; Gilbertson, 1983.

⁴⁹ Fanelli et al., 1980.