by Beth Ann Filiano
Environmental Sciences
Columbia University School of Public Health
3 December 1996
Introduction
Dioxin, which has been called the most toxic substance ever created by humans, is a class of halogenated aromatic hydrocarbons. The most potent, most studied of these compounds is 2,3,7,8-Tetrachlorodibenzo-p-dioxin (or TCDD, or often referred to simply as dioxin). This is one of the contaminants present in Agent Orange, the defoliant used extensively during the Vietnam War, and which is thought to be the cause of a variety of health problems experienced by veterans of this war.[19] The effect of dioxin on human health is still being debated by scientists. The EPA is in the process of reviewing their position on the toxicity of dioxin and on acceptable levels of exposure. The initial report which resulted was criticized by many scientists for being alarmist and unscientific in reviewing the data collected.
Recently, some attention has been drawn to the presence of dioxins in tampons. Dioxin is a by-product of the chlorine bleaching process used to bleach tampons. In 1992, a congressional committee examining the public health risk of dioxin came across FDA reports which had previously not been made public. In these studies, there were trace levels of dioxin found in commercially produced tampons. There were memos discovered which indicated that as far back as 1989, scientists at the FDA believed that the risk of the presence of dioxin in tampons was high, and that further studies testing such levels needed to be done. The FDA never pursued this issue. Instead, they relied on data provided by US tampon manufacturers. The panel's conclusion was that there was no health risk to women from dioxin in tampons.[7] In July of this year, Representative Carolyn Maloney (D-NY-14) sponsored a bill entitled "The Woman's Health and Dioxin Act of 1996," which called for research into the presence of dioxin in menstrual products and the potential health effects for women using these products. Currently, the tampon industry faces surprisingly little regulations from the FDA (menstrual products are considered medical devices, and as such, fall under the FDA's regulation).[14] Both the industry and the FDA have failed to protect women from negative health effects in the past; in 1980, 38 women died from tampon-related toxic shock syndrome. There was a class action suit filed against the manufacturers of Playtex and Tampax tampons, alleging that companies knew of the increased risk of TSS posed by super-absorbent rayon fibers used in most tampons today for more than ten years.[7] Given this history of overlooking or downplaying the risk to women from menstrual products, as well as the marginalization of many other women's health issues, it seems reasonable to assume that an objective analysis of the presence and effects of dioxin in these products is needed, and the regulatory mechanisms and guidelines for this industry need to be evaluated and reformed to better protect women's health.
Toxicity: Molecular Mechanisms, Animal Models, and Human Cohorts
The toxic effects of dioxin and doses vary widely between species studied, and the mechanism for this range of toxicities is only beginning to be understood. Toxic effects include alterations in metabolic pathways, immunological changes, teratogenic effects and abnormal cell growth.[20] It has been proposed that on the molecular level, TCDD works by a receptor mediated mechanism both in the nucleus as transcription factor, and in the cytoplasm as a regulator of second messengers such as tyrosine kinase.[2, 20]
The biochemical effects of dioxin can be grouped into three types of responses: those involving enzymes, growth factors, and hormones.[20]
The induction of enzymes by dioxin obviously affects the biochemistry of the cell. For example, changes in the levels of enzymes which regulate cell growth and differentiation have been shown. Differences in levels of growth factors, such as epidermal growth factor, growth factor receptors, cytokines and protooncogene expression has also been shown with exposure to dioxin. These also effect cell growth and differentiation. Such changes could be the cause of immunotoxic, teratogenic, and carcinogenic responses to dioxin. [2]
Changes in hormone levels have been shown to result from dioxin exposure. These are again tissue and species specific. The only generalization which can be made about the effect of dioxin is that it seems to act as an endocrine disrupter, and that the changes in hormone and receptor levels results in altered homeostasis, which is the network of complex feedback mechanisms of the body to maintain a stable, constant equilibrium of these hormones.[2]
The receptor to which TCDD binds was found to be the Ah receptor, or aryl hydrocarbon receptor. [10] A simple example of the pathway by which TCDD acts as a transcription factor was studied in mice, in the induction of microsomal aryl hydrocarbon hydroxylase (AHH) activity. Hydroxylase activity is the first step in the metabolysis of fat soluble polycyclic hydrocarbons to water soluble products. When TCDD binds to an Ah receptor in the cytoplasm of the cell, the complex moves into the nucleus, where it associates with a third protein and activates gene transcription. [2] This model is a relatively simple and straight forward example of one of the pathways by which dioxin may produce its effects. Tissue-specific effects and the wide range of TCDD's biological effects point to a complex interaction between genetic and environmental factors; therefore although molecular models are important for understanding how dioxin may work on a cellular level, assessing potential effects in humans requires looking at molecular and animal models, along with human populations which have been exposed to known levels of dioxin. [10, 16]
Effects of dioxin have been studied in different animal models, with widely varying results. High exposure to TCDD can cause fetal death in all species studied.[2] There also seems to be negative effects to reproduction in all species studied.[2] The number of pregnancies in rats which had been exposed to TCDD in utero was significantly lower; exposure to dioxin early in development also affected dopamine regulation (dopamine is used as an indicator of neurotransmitter function).[13] In mice, low doses (defined as non-toxic doses) cause structural defects. The best described example of this is cleft palate. A proposed mechanism by which dioxin causes this defect is through a change in differentiation and proliferation of epithelial cells.[2] Effects on the thymus, spleen, and kidneys were shown in several species.[2] An interesting study, especially when looking at the health risk for dioxin exposure via tampon use shows a correlation between exposure to dioxin and endometriosis in rhesus monkeys. A dose response was also clearly shown.[12]
It is difficult to predict toxic effects and doses of dioxin in humans even by looking at molecular and animal models together. There have been large scale human exposures to dioxin such as the chemical plant explosion in Seveso, Italy in 1976. The studies from this population focus on incidences of cancer. The overall risk for developing cancer does not appear significantly higher, but the rates of certain cancers are increased, such as a type of myeloma in women, cancers of the blood in men, and liver cancer in general.[17] One of the greatest limitations in these studies is the inability to accurately determine levels of exposure at the time of the incident (levels were estimated by soil concentration), but current methods of detection have made it easier to detect levels in blood more accurately, and analysis of current blood levels correspond to predicted estimates.[5]
Currently, there is only indirect evidence linking exposure to dioxin with endometriosis in humans. There was a study in Germany which showed that women with high levels of polychlorodiphenyl compounds in their blood have a greater than normal incidence of endometriosis.[6] According to a report from the WHO, Belgian women have the highest dioxin levels in breast milk in the world; the incidence of endometriosis in Belgium is also one of the highest.[9] Specific studies on the health effects of dioxin on women have not been done, although more recently the reproductive, developmental, immune and endocrine effects have increasingly been the focus of dioxin research. There is currently a study on dioxin-exposed women in Seveso.
(Editor's note: A press release from the International Agency for Research on Cancer on February 14, 1997, states that TCDD is carcinogenic to humans and increases the overall risk of cancers. The results are to be published in Volume 69 of the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.)
Endometriosis is the growth and proliferation of endometrial cells outside the uterus, in the ovaries, bladder, intestine, and pelvic peritoneum. These cells still respond to ovarian hormones; they undergo cyclic menstrual changes, with periodic bleeding. This disease is only beginning to be understood. The cause of the cellular migration is unknown; one theory is that it results from a backward flow of menstrual blood.[6] There are mild and severe cases of this disease, whose symptoms include chronic pain and infertility. Because many women experience menstrual pain and endometriosis can only be accurately diagnosed by laparoscopy, the incidence in the general population is unknown. It is estimated, however, that the rate may be as high as 10% of all reproductive-age women.[12] Since dioxin appears to have an effect on the endocrine system, it seems increasingly important that studies of the effects on women be conducted.
EPA's reassessment of dioxin's toxicity
In 1991, the EPA began to review the health risks of dioxin. The conclusion that they reached after 4 years is that dioxin does pose a risk to human health. The question of whether dioxin is a carcinogen at low doses was not answered; but evidence from animal studies indicates that dioxin's non-carcinogenic effects could have a more harmful effect on human health.[15] The EPA's report received much criticism from many scientists, many of whom believe that there is no clear evidence showing toxic effects of dioxin in humans. Molecular toxicology, and the receptor model for dioxin's toxicity indicate that there should be a threshold on dioxin response.[8,11,16,18] It seems from reviewing the literature (including the commentaries and letters in Science and Nature) that there is no definitive answer to the question of dioxin's health risk to humans. Molecular toxicology is a relatively new field, which combined with more traditional animal studies and epidemiological studies may lead to a better understanding of this complex class of compounds.
Conclusions
The questions about toxic effects and mechanisms of dioxin in the human system has no simple answer; current research does seem to indicate that viewing dioxin as the most toxic substance on earth is extreme, but there are serious environmental and health effects. Molecular evidence that dioxin works by a receptor-mediated pathway suggests that there should be threshold effect, though this has not yet been shown in humans. It does seem reasonable, however, that the possible correlation between dioxin and endometriosis should be further examined. Since it is neither possible nor desirable to perform controlled studies on dioxin exposure in humans, it will be difficult to conclusively determine the relationship between dioxin and endometriosis and other reproductive health problems. This is especially true since both mechanisms for dioxin's effects and endometriosis are only now beginning to be understood. Dioxin has an effect on hormone regulation in every species studied.[2] The cause of endometriosis is unknown, but the incidence of this disease is increasing. Although there is only indirect evidence in humans linking dioxin to endometriosis, taken with the strong correlation between levels of dioxin and severity of disease in rhesus monkeys, again it is reasonable to conclude that there could be a connection between the two in humans. Exposure to dioxin by tampon use is an unnecessary and avoidable risk; introducing dioxin directly into the reproductive tract seems like a very foolish thing to do, especially when there have been no studies on the effects of dioxin in human women.
It is necessary for women to take an active role in educating themselves and protecting their health. Women's health issues are often marginalized in both the legislative and regulatory bodies. Changes need to occur on many levels. The bill introduced by Rep. Maloney, calling for independent research into levels of dioxins present in tampons from the chorine bleaching process and the effects of this presence on women's health, is a good start. In addition, standards for regulating current menstrual products and the introduction of new products without the proper safety evaluations need to be changed. It is also necessary as consumers to demand safe products. I became aware of this issue from a small health article in Ms. profiling the president of a small Canadian company1 which produces all cotton, non-chlorinated menstrual products. It is important to act by purchasing such products and boycotting companies which market chlorinated tampons, because past experience in the case of toxic shock syndrome has shown the dangers of allowing the tampon industry to regulate itself. It's also necessary to educate others, and especially to discuss reproductive and women's health issues in an open environment.
[1] Biobiz (www.biobiz.com/terrafemme/biobus.htm).
[2] Birnbaum LS: Developmental effects of dioxin. Environmental Health Perspectives, 103: suppl 7: 89-94 (1995).
[3] Dioxin and endometriosis. Environmental Health Perspectives, 101: 7: 571-572 (1993).
[4] Gibbons A: Dioxin tied to endometriosis. Science, 262: 5138:1373 (1993).
[5] Holloway M: Dioxin indictment: a growing body of research links the compound to cancer. Scientific American, 270: 1: 25 (1994).
[6] Holloway M:An epidemic ignored. Scientific American, 270: 4: 24-26 (1994).
[7] Houpert K: Embarrassed to death: the hidden dangers of the tampon industry. Village Voice (February 7, 1995).
[8] Kolbye AC: ISRTP Council comments regarding "A public health and regulatory perspective on risk of dioxin-like compounds." Regulatory Toxicology and Pharmacology, 21: 322-324 (1995).
[9] Koninckx PR, Braet P, Kennedy SH, Barlow DH: Dioxin pollution and endometriosis in Belgium. Human Reproduction, 9: 6: 1001-1002 (1994).
Mackler C: Willi Nolan:"out damned dioxin! Ms., 7:2: 42 (1996).
[10] Marshall E: Toxicology goes molecular. Science, 259: 5100: 1394-1398 (1993).
[11] Reichhardt T: EPA rebuffs challenge to its assessment of dioxin data. Nature, 371: 6495: 272 (1994).
[12] Rier SE, Martin DC, Bowman RE, Dmowski WP, Becker JL: Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fundamental and Applied Toxicology, 21: 443-441 (1993).
[13] Sauer PJJ, Huisman M, Koopman-Esseboom C, Morse DC, Smits-van Prooije AE, vande Berg KJ, Tuinstra LGMTh, van der Paauw CG, Boersma ER, Weisglas-Kuperus N, Lammers JHCM, Kulig BM, Brouwer A: Effects of polychlorinated biphenyls (PCBs) and dioxins on growth and development. Human and Experimental Toxicology, 13: 900-906 (1994).
[14] S.P.O.T. (http://critpath.org/~tracy/spot.html): Dioxin reassessed: an overview.
[15] Stone R: Dioxin report faces scientific gauntlet. Science, 265: 5179:1650 (1994).
[16] Stone R: A molecular approach to cancer risk. Science:, 268:5209: 356- 357 (1995).
[17] Stone R: New Seveso findings point to cancer. Science, 261: 5139: 1383 (1993).
[18] Stone R: Panel slams EPA's dioxin analysis. Science, 268: 5214: 1124 (1995).
[19] Tschirley FH: Dioxin. Scientific American, 254: 2: 29-35 (1986).
[20] Whitlock, JP Jr: Mechanistic aspects of dioxin action. Chemical Research in Toxicology, 6: 6: 754-763 (1993).