The Dioxin and Endometriosis Studies

The following 18 studies indicate a possible link between dioxin exposure and the development of endometriosis, just as the previous section found links for PCB exposure. Certain PCBs are dioxin-like. In addition, PCB mixtures are often contaminated with dioxins. See PCBs, Dioxins, Furans and Mercury --- They Travel Together. Keep in mind that the studies are not all equal in quality. Some studied total PCBs while others focussed only on certain varieties of the 209 kinds of PCB. This is not a complete list of all studies on this topic. For more, visit the TOXNET database operated by the National Library of Medicine (the source of these abstracts). For more information, see Endometriosis Introduction.
Study #1
endometriosis is directly linked to dioxin exposure, and dose-dependent The incidence of endometriosis was determined in a colony of rhesus monkeys clinically exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin ... for a period of 4 yr. Ten years after termination of dioxin treatment, the presence of endometriosis was documented by surgical laparoscopy and the severity of disease was assessed. The incidence of endometriosis was directly correlated with dioxin exposure and the severity of disease was dependent upon the dose administered (p< 0.001). Three of the seven animals exposed to 5 parts per trillion dioxin (43%) and 5 of 7 animals exposed to 25 parts per trillion dioxin (71%) had moderate to severe endometriosis. In contrast, the frequency of disease in the control group was 33%, similar to an overall prevalence of 30% in 304 monkeys housed at The Harlow Primate Center with no dioxin exposure. This 15 yr study indicates that latent female reproductive abnormalities may be associated with dioxin exposure in the rhesus. (Rier et al, 1993)
Study #2
endocrine disruptors are implicated in endometriosis A rise in industrialization and the consequent environmental pollution, an increase in the use of synthetic chemicals and repeated exposure to hazardous compounds at the workplace and at home adversely affects reproductive health. Biohazardous compounds, some of which act as endocrine disrupters, are being increasingly implicated in infertility, menstrual irregularities, spontaneous abortions, birth defects, endometriosis and breast cancer. In some cases, women are at a greater risk than men, especially with the rise in environmental estrogens. Only a fraction of these chemicals have been adequately examined for toxicity and for synergistic effects due to multiple exposures. There is a need for a greater awareness and vigilance of the effects of environmental pollution on reproductive health. (Bhatt, 2000)
Study #3
dioxin or dioxin-like compounds (certain PCBs) are associated with endometriosis This summary report focuses on current studies on reproductive effects reported at the workshop on Perinatal Exposure to Dioxin-like Compounds and supporting data noted in the discussion. Recent laboratory studies have suggested that altered development (e.g., low birth weight, spontaneous abortion, congenital malformation) and reproductive health (e.g., fertility, sex organ development, reproductive behavior) may be among the most sensitive end points when examining the effects of dioxinlike compounds. Thus, future research should target the reproductive health of both males and females exposed postnatally and prenatally. Studies in humans are needed and are on-going. In animal models, postnatal exposure to dioxin or dioxinlike compounds has been associated with abnormal spermatogenesis and abnormal testicular morphology and size in males and with reduced fertility and endometriosis in females. In utero exposure may also produce profound reproductive consequences in both males and females including delays in sexual maturation, abnormalities in development of sexual organs, and abnormal sexual behavior. The mechanism by which dioxin-like compounds cause reproductive effects is not well delineated. (Eskenazi et al, 1995)
Study #4
endometriosis increases in female offspring of dioxin-fed mothers
dioxin increases the size of endometriotic lesions Several lines of research led to our hypothesis that perinatal exposure to TCDD may alter the sensitivity of adult rodents to the promotional effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on endometriosis. Pregnant rats and mice were treated on gestation day (GD) 8 with either 1 (rats) or 3 (mice) microg TCDD/kg or vehicle. Female offspring were reared to adulthood, and endometriosis was induced surgically. All animals received 0, 3, or 10 microg TCDD/kg 3 weeks prior to surgery, at the time of surgery, and 3, 6, and 9 weeks after surgery. Necropsies were performed 12 weeks after surgery. Measurements at necropsy included the diameter of endometriotic lesions and body, uterine, ovarian and liver weights. While no effect of treatment on lesion diameter was found in rats, analyses revealed that perinatal plus adult exposure to TCDD can increase the size of endometriotic lesions surgically induced in mice. These and additional data on body and organ weights are consistent with previous work. These data confirm the sensitivity of mice to the promotion of endometriotic lesion growth by TCDD and indicate a perinatal effect of TCDD on this parameter when perinatal exposure on GD8 is supplemented with adult exposure to TCDD of female mice. (Cummings et al, 1999)
Study #5
dioxin increases the incidence and severity of endometriosis
human rates of endometriosis have increased during the last decades Dioxins are a family of chlorinated aromatic hydrocarbons that are produced during combustion processes in the presence of a chlorine donor and as by-products of the chlorine-processing chemical industries. Several dioxins are extremely stable compounds and persist for years in the environment. Exposure to dioxins occurs mainly via the ingestion of contaminated food. The lipophilic character of dioxins prevents their excretion in the urine and causes their accumulation in body fat. The mechanisms of dioxin action are similar to those of a hormone. Dioxins bind to a specific intracellular receptor and the complex acts as a transcription factor that induces the production of a great number of proteins. Certain dioxins, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin, are very toxic and able to induce numerous clinical conditions. The carcinogenicity of dioxins is well documented in animal models and has been described in humans after professional and accidental exposures. Recent experimental data also indicate that dioxins can cause dysfunction of the sexual and thyroid hormone systems and that the administration of dioxins induces several conditions related to hormonal dysfunction. Chronic exposure of female Rhesus monkeys increases the incidence and severity of endometriosis. The administration of dioxins during pregnancy and nursing causes altered development of the reproductive system, decreased spermatogenesis, hypothyroidism and disturbed psychomotor development in the offspring. The particular sensibility of the fetus and newborn is of concern because the exposition to dioxins is particularly important during those periods of life. In humans a series of conditions related to hormonal dysfunction as undescended testis, decreased spermatogenesis, testicular cancer and endometriosis have increased in incidence during the last decades. The chronological parallelism with the appearance of dioxins in the environment suggests that these might exert biological effects at the prevailing level of exposure. Nevertheless this hypothesis is currently unconfirmed by epidemiological studies. The implications of this scientific incertitude for the implementation of preventive measures are briefly discussed. (Wissing, 199
Study #6
the dioxin margin of safety is insufficient to protect against endometriosis The human health risk of dioxins was evaluated for four Japanese receptor groups: the general population, local residents living near a municipal solid waste incinerator, heavy fish consumers, and their infants and fetuses. In describing the risk for these groups, four endpoints, namely, cancer, reproductive dysfunction, endometriosis and neurobehavioral effect, were considered, and the incremental cancer risk and margin of exposure (MOE) corresponding to these endpoints were calculated, based on three measures of dosimetry; average daily intake, area under the curve, and body burden. The uncertainties of these risk descriptors were also evaluated by probabilistic analysis. Although the estimated risk of cancer and reproductive dysfunction were not exceptionally high in the three adult receptor groups, the MOE values for endometriosis were not sufficiently high to guarantee safety against this endpoint. Furthermore, the MOE values for neurobehavioral effects on infants and fetuses suggest that dioxins may cause a considerable risk to those of local residents and heavy fish consumers. (Yoshida et al, 2000)
Study #7
dioxin is correlated with an increased incidence of endometriosis The aim of this study was to determine whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) exposure exerts detrimental effects on folliculogenesis in the Holtzman rat ovary. TCDD is a potent modulator of reproduction and an endocrine disrupter. In certain species, this dioxin has been shown to reduce fecundity. Further, TCDD exposure is correlated with an increased incidence of endometriosis and various reproductive cancers. Our laboratory previously reported that TCDD effects are in part mediated at the level of the ovary and we have observed increased estrogen receptor mRNA but diminished circulating estrogen concentrations. We hypothesize that the reduction in estrogen secretion with TCDD is attributable to a decreased number of healthy follicles in the ovary. An oral dose of 1 ug TCDD/kg maternal body weight was administered on day 15 of gestation. Female pups were sacrificed on post-natal day 21-23 and the ovaries were removed and fixed in Bouin's solution. The ovaries were dehydrated in a graded series of ethanol concentrations and infiltrated with xylene and paraffin. The tissues were then sectioned at 10 um and stained with eosin and hematoxylin. Follicles were analyzed in a double-blind paradigm. The analysis included a count, measurement and classification of pre-antral and antral follicles throughout the entire ovary. Greatest cross-sectional area of each follicle was calculated as pi(A)(B), where A and B are one-half the greatest length and width of the section containing the germinal vesicle. TCDD treatment significantly reduced the number of antral follicles in the size classes 75,000-99,999 um2 and greater than 100,000 um2 using X2 goodness-of-fit. We also observed a reduction in the number of follicles less than 50,000 um2 regardless of classification. These data support the hypothesis that TCDD inhibits the growth of certain classes of ovarian follicles in animals exposed during critical periods of development. (Trewin et al, 1996)
Study #8
dioxin is correlated with an increased incidence of endometriosis Recent reports have described the reproduction-modulating and endocrine-disrupting effects following exposure to toxic substances such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Herein, we set out (1) to determine whether TCDD exposure exerts detrimental effects on follicle maturation in the Holtzman rat ovary and (2) to determine whether the effects of TCDD are mediated in part via apoptotic cell death. In certain species, dioxin exposure is correlated with reduced fecundity, reduced ovulatory rate, an increased incidence of endometriosis, and various reproductive cancers. Although some of the effects of TCDD are mediated via the hypothalamic-pituitary axis, direct effects on the ovary have also been observed. In the present study, an oral dose of 1 microgram TCDD/kg maternal body weight was administered on Day 15 of gestation. Female pups were sacrificed on Postnatal Day 21/22, and the ovaries were excised, fixed for histologic analysis, and analyzed in a double-blind paradigm. The analysis included a count and measurement and classification of preantral and antral follicles throughout the entire ovary. The contralateral ovary from each animal was analyzed for DNA fragmentation indicative of apoptotic cell death. The results indicate that TCDD treatment significantly reduced the number of antral follicles in the size classes 50,000 to 74,999 microns2 and > 100,000 microns2. We also observed a reduction in the number of preantral follicles less than 50,000 microns2. No difference was
observed in the degree of apoptotic cell death in antral (50,000 to > 100,000 microns2) and preantral follicles (50,000 microns2 to > 75,000 microns2) between TCDD-treated and control-treated tissues. These data support the hypothesis that TCDD results in a diminution in the number of antral and preantral follicles of certain size classes in animals exposed during critical periods of development, but that apoptosis does not appear to be the underlying mechanism in these particular follicles. This does not preclude apoptosis occurring in pools of smaller precursor follicles. (Heimler et al, 199
Study #9
dioxin enhanced cystic endometrial hyperplasia Exposure to pesticides or toxic substances that disrupt the endocrine system during sex differentiation can permanently alter reproductive function and produce morphological pseudohermaphrodism. While some developmental toxicants affect either the male or the female, in utero exposure to 0.5 micrograms TCDD/kg/day from Gestational Day (GD) 6 to GD 15 induces infertility in both sexes (K.S. Khera and J.A. Ruddick, Chlorodioxins--Origins and Fate, pp. 70-84, Am. Chem. Soc., Washington, DC, 1973). Although a number studies have focused on the effects of a single dose of TCDD on sex differentiation of the male rat and hamster, the reproductive alterations that account for female-mediated infertility after in utero exposure to TCDD have not been described. Hence, it was our objective to describe the anatomical and functional reproductive alterations in female progeny after gestational administration of TCDD. In the first experiment, LE Hooded rats were given a single dose of 1 microgram TCDD/kg by gavage on CD 8 (i.e., a period that includes major organogenesis) or GD 15 (i.e., a period prior to sex differentiation and a dosing regime that alters sex differentiation of the male LE rat). In a second experiment, Holtzman rats were dosed with TCDD at 1 microgram/kg on GD 15, to determine if the progeny of this strain displayed malformations of the external genitalia and vaginal orifice as did LE rats. TCDD-treated female LE offspring displayed a number of unusual reproductive alterations. In the GD 15 group, puberty was delayed, more than 65% of the female offspring displayed complete to partial clefting of the phallus, and 80% displayed a permanent "thread" of tissue across the opening of the vagina. In the GD 8 treatment group, 25% displayed partially cleft phallus and 14% had a vaginal thread. GD 15 TCDD administration also induced a high incidence of malformations in Holtzman female progeny (100% clefting and 83% with a vaginal thread). At necropsy ( > 550 days old), ovarian weight was significantly reduced by 23% in both rat strains. In the LE rat, vaginal and behavioral estrous cyclicity, estrous cycle-mediated running wheel activity, and female sexual behaviors at proestrus (darting and lordosis to mount ratios) were not affected by gestational GD 15 TCDD treatment. However, untreated stud males had difficulty attaining intromission and took longer to ejaculate and vaginal bleeding was displayed during mating by GD 15 TCDD-exposed female offspring. GD 8 TCDD-treated female offspring displayed enhanced incidences of constant estrus (CE) (47% CE in GD 8 versus 16% CE in the control and GD 15 groups at middle age) and cystic endometrial hyperplasia. In addition, in the GD 8 group the fertility rate declined significantly faster than in controls (p less than 0.02) and fecundity was reduced by 38% (p less than 0.07). In conclusion, administration of a single dose of 1 ug TCDD/kg on GD 15 results in malformations of the external genitalia in female LE and Holtzman rats. While GD 15 treatment is generally more toxic than GD 8 to the offspring with respect to growth, viability, male reproductive effects (L. E. Gray, W. R. Kelce, E. Monosson, J. S. Ostby, and L. S. Birnbaum, Toxicol. Appl. Pharmacol. 131, 108-118, 1995) and malformations of the external genitalia in the female progeny, treatment on GD 8 is more effective in inducing functional reproductive alterations in female progeny. (Gray et al, 1995)
Study #10
expression of AhR and dioxin-related genes in the endometrium did not differ in women with or without endometriosis 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been suggested as a possible etiologic factor for endometriosis, a condition in which endometrium-like tissues are present outside the uterus. The prevailing view pertaining to the origin of endometriotic cells is that they are from eutopic endometrial cells which regurgitate through fallopian tubes. In order to get insight into the possible involvement of TCDD in the pathogenesis of endometriosis, we suspected that TCDD may act differently on the endometrium with or without endometriosis. To address this, we examined the presence of messenger RNAs of arylhydrocarbon receptor (AhR), AhR nuclear translocator (Arnt) and two dioxin-responsive genes, cytochrome P-450 1B1 (CYP1B1) and downstream of tyrosine kinases (p62(dok)), in the endometrium of women with or without endometriosis using semi-quantitative reverse transcription-polymerase chain reaction. All the genes were expressed throughout the menstrual cycle. The expression level of p62(dok) was higher in the proliferative phase than in the secretory phase. In contrast, the expression levels of AhR, Arnt and CYP1B1 seemed to be constant during the cycle. In terms of the comparison between non-endometriosis and endometriosis group, the mRNA levels of AhR, Arnt, CYP1B1 and p62(dok) were essentially similar. Interestingly, AhR mRNA level was significantly lower in smokers than in non-smokers. Based on the regression analysis, significant linear and positive correlations were observed between AhR and Arnt mRNA levels, and between Arnt and p62(dok) mRNA levels. In summary, expression of AhR and dioxin-related genes in the endometrium did not differ in women with or without endometriosis. (Igarashi et al, 1999)
Study #11
dioxin facilitates survival of endometrial implants
dioxin promotes growth in diameter of endometrial implants An increase in the incidence and severity of endometriosis following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was a serendipitous finding in a reproductive toxicology study in rhesus monkeys. The purpose of this study was to investigate the effects of subchronic exposure to TCDD on the survival and growth of surgically implanted endometrial fragments. Endometrial fragments of equal size (4 x 1 mm(2)) were auto-transplanted to the pelvic cavity of nulliparous cynomolgus monkeys (Macaca fascicularis, n = 23), who were divided into 4 treatment groups and dosed 5 days a week with gelatin capsules containing 0, 1, 5, or 25 ng/kg body weight of TCDD mixed with glucose. Endometrial implant survival was monitored by laparoscopy at intervals of 1, 3, and 6 months. Animals were euthanized at 12 months of treatment in the early to mid luteal phase and the maximal and minimal endometrial implant diameter was measured. Both the maximal and minimal diameters were significantly reduced in the 0.71-ng/kg/day-TCDD dose group, compared to controls, whereas the survival rate was unaffected (20 vs. 16%, respectively). In contrast, exposure to 3.57 and 17.86 ng/kg/day TCDD for 1 year resulted in a significantly higher survival rate of implants (26.7% and 33.3% respectively vs. 16.0%) and significantly larger diameter implants in the 17.86-ng/kg/day dose group only, compared to the control group. Treatment had no effect on circulating gonadal steroid levels or menstrual cycle characteristics. It is concluded that TCDD facilitates the survival of endometrial implants and exerts a bimodal effect on endometrial implant growth. (Yang et al, 2000)
Study #12
dioxin exacerbates endometriosis
increased endometriotic site diameter
dose-dependent increase in endometriotic growth
reduced ovary weight
persistent estrus
ovulatory arrest
hemorrhage and necrosis of the endometrial lining
fibrosis
reduced thymus weight
increased liver weight
reduced body weight gain The influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (1746016) (TCDD) on surgically induced endometriosis was examined. Female Sprague-Dawley-rats and B6C3F1-mice were gavaged with TCDD at 0, 3, and 10 micrograms per kilogram body weight (microg/kg), both before and after surgery. Rats were sacrificed from 3 to 12 weeks after surgery. Controls were treated with surgery but not with TCDD. At a dose of 10microg/kg, TCDD significantly increased endometriotic site diameter in rats. However, this effect was determined only when all time points were pooled. In mice, TCDD treatment induced a significant, dose dependent increase in endometriotic site growth 9 and 12 weeks after surgery. Compared to controls, ovarian weight decreased in rats treated with either 3 or 10microg/kg TCDD, at both 9 and 12 weeks after surgery. Persistent estrus at necropsy was common in rats exposed for 9 and 12 weeks. Ovulatory arrest was discerned in 45% of the treated rats and 11% of the controls. TCDD did not exert a significant effect on the ovarian weight or estrus cycle of mice. While endometriotic sites exhibited endometrial fibrosis in both controls and treated rats, hemorrhage and necrosis of the endometrial lining were observed only in rats treated with TCDD. Fibrosis, not observed in control mice, was detected in treated mice. Compared to the organ weights of controls, the thymus glands of treated animals weighed significantly less, while the livers of treated animals weighed significantly more. After 9 and 12 weeks of treatment with 10microg/kg, the body weight gain of rats decreased significantly. The authors conclude that TCDD exacerbates surgically induced endometriosis in both rats and mice. The mouse is the model of choice for further study concerning the effects of TCDD exposure on endometriosis. (Cummings et al, 1996)
Study #13
dioxin increases enzymes which promote endometriosis Environmental contaminants that are known to disrupt steroid action can influence the development of reproductive diseases. Our group has focused on whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) can disrupt steroid regulation of endometrial matrix metalloproteinase (MMP) expression. The MMPs regulate extracellular matrix turnover in normal tissues, but the inappropriate expression of these enzymes is associated with numerous disease states that involve invasive processes. We have previously shown that secretion of MMPs by human endometrium is critical for establishment of ectopic lesions in a nude mouse model of experimental endometriosis. In this report, we show that TCDD exposure promotes establishment of experimental endometriosis by interfering with the ability of progesterone to suppress endometrial MMP expression. (Bruner-Tran et al, 1999)
Study #14
dioxin is associated with endometriosis in humans The concentrations of the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin were measured in the blood of 44 infertile women with endometriosis (study group), and in 35 age-matched women with tubal infertility (control group). Eight women with endometriosis (18%) were dioxin positive as compared to one woman (3%) in the controls (P = 0.04). Although the concentrations of dioxin did not seem to be directly correlated with the severity of endometriosis, these observations contribute to the accumulating data linking dioxin to endometriosis in humans. (Mayani et al, 1997)
Study #15
environmental toxins affect the response of the endometrium to steroids, resulting in endometriosis The proper function of the normal human endometrium relies on well organized cell-cell interactions regulated locally by cytokines and growth factors under the direction of steroid hormones. The onset and progression of the disease processes of endometriosis may result from disruptions of this well balanced cellular equilibrium. Evidence continues to accumulate indicating that environmental toxins, whether naturally occurring or man-made, may directly (hormone disruptor) or indirectly (immune toxin) affect the response of the endometrium to steroids, resulting in various pathological states including endometriosis. (Osteen et al, 1997)
Study #16
study review The effect of natural, environmental, or manufactured substances on endocrine organs is a current topic of discussion. Recently, some toxicants have been suggested to promote endometriosis; therefore, attention has turned to the role of environmental factors as a stimulant for endometriosis growth and maintenance. This article reviews the influence of various toxicants on endometriosis. (Zeyneloglu et al, 1997)
Study #17
study review Reports in the literature of an increasing incidence of endometriosis in industrialized countries and increasing problems with pollution in these countries leads to speculation about a possible link between one of the most harmful components of pollution, dioxin, and endometriosis. To establish this link, we need to examine three issues more closely: What are the effects of dioxin, what is the true incidence of endometriosis, and what is the nature of the association between endometriosis and dioxin. This report reviews current thinking on these issues. (Koninckx, 1999)
Study #18
Concludes with "the possibility that the ingestion of dioxin-like compounds causes adverse health effects in the Dutch population cannot be excluded with reasonable certainty."
Cites report of Rhesus monkeys developing endometriosis after dioxin exposure Effects and recommended exposure limits. Dioxin-like substances are frequently present in the environment in the form of mixtures of many polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and the dioxin-like polychlorinated biphenyls (PCBs). Exposure to these compounds may have various adverse health effects, depending on the dose. A great deal of research has been done on the carcinogenic properties of these substances and their effects on reproduction and prenatal and postnatal development. These studies show that developmental effects are the first to be observed as a result of increased exposure, especially in the case of young infants. If exposure increases any further, the promotion of cancer can - after a certain level - no longer be excluded. The toxic equivalent of a mixture. The effect of the various substances is rather diverse, but it is certain that the many dioxin-like substances act in a similar way on body cells. This finding, together with the fact that the chemicals in question frequently appear in mixtures of highly diverse composition, has led to the adoption of a group approach. One aspect of this approach, supported by the Committee, is the assignment of a toxic equivalency factor (TEF) to each dioxin-like substance. The TEF value expresses toxicity in relation to the most toxic substance of the group, 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). The toxic equivalent (TEQTOTAL) of a mixture of PCDDs, PCDFs and dioxin-like PCBs is determined by multiplying the concentration found for each individual compound by the relevant TEF value and adding up the resulting products. The Committee deems the TEF concept to be applicable to the assessment and limitation of the risks associated with exposure to these substances by humans and by animals and ecosystems. Experimental data show that the TEFs for man, fish and birds can differ substantially. The Committee therefore believes that in estimating the ecotoxicological risk, TEFs other than those used for the toxicological evaluation for humans should be employed. The Committee supports the internationally agreed TEF values for humans; however, it believes that further research is needed before ecotoxicological TEFs can be used. Humans. It is government policy to guarantee with reasonable certainty that an intake equal to the health-based recommended exposure limit for a particular substance will have no adverse effect on the health of the exposed persons or their offspring. Concerning dioxin-like substances the Committee judges an 'adverse effect' to be each observable change which immediately or in the longer term is harmful to an organism, as well as each adaptation or response by the organism to exposure to these chemicals which may not with reasonable certainty be regarded to be harmless. On the basis of animal data, the Committee derives a recommended limit of human exposure to dioxin-like compounds of I picogramme of toxic equivalents per kilogramme of body weight per day. This value is lower by a factor of 10 than the figure recommended by the World Health Organisation (WHO), and the RIVM. The Committee underpins its proposal with the results of other animal studies, some of which are more recent than those used by the WHO. The Committee arrived at its proposed health-based recommended exposure limit in the following way. Exposure to dioxin-like substances at low dose levels does not cause cancer, but at these intake levels there may be other adverse effects. For instance, changes have been observed in the cognitive development of Rhesus monkeys when the mother was exposed to approximately 100 picogrammes per kilogramme of body weight per day or more. The mothers developed endometriosis. In another study changes in the white blood cells of Marmoset monkeys were observed at a similar level of exposure. The Committee takes the 100 picogramme level per kilogramme to be the lowest level at which adverse effects have been observed. In order to derive a recommended level for humans from the reported animal studies, the Committee made use of extrapolation and safety factors. Using dose-response ratios for effects on rats in the lower intake range, it derived an extrapolation factor from 'lowest observed adverse effect level' to 'no adverse effect level' of 2 for experimental animals. Application of this figure to the above data for monkeys thus gives a 'no adverse effect level' of 50 picogrammes per kg. of body weight per day. The Committee then selected a factor of 5 for extrapolation from monkey to man. Monkeys appear to be closer to man with regard to the distribution of PCDDs and PCDFs between the liver and fatty tissue than, for instance, rats. Thus, the Committee does not employ the usual factor of 10 for extrapolation from rat data. Differences in sensitivity between humans (intraspecies variation) are accounted for by applying the usual safety factor of 10. This reasoning leads to a figure of I picogramme per kg. of body weight per day as a public health-based exposure limit for humans. Ecosystems. Government policy is to limit the exposure at a level at which with reasonable certainty at least 95% of the species in an ecosystem will not experience adverse effects from the substance. Ecotoxicology based recommended exposure limits are the basis for that. The Committee uses fixed extrapolation factors in deriving these limits, taking the data on 2,3,7,8-TCDD for a sensitive species as the basis. For 2,3,7,8-TCDD in aquatic ecosystems, the Committee has derived a recommended exposure limit of 0.1 picogrammes per litre of water and 13 000 picogrammes per 1 kilogramme of dry matter in the sediment. In establishing these concentrations it took into account the possibility of accumulation of the chemical in the food chains and the consequences of that on birds and mammals. The Committee proposes using an ecotoxicology based recommended exposure limit of 2000 picogrammes of 2,3,7,8-TCDD per kilogramme of dry matter for terrestrial ecosystems. Here, too, it has taken accumulation in the food chain into account. An important difference between the exposure limits in this report and those in the RIVM criteria document on Dioxins is the fact that the Committee derives ecotoxicological exposure limits for 2,3,7,8-TCDD. Only for this substance there are enough data. In some aquatic ecosystems however the exposure to dioxin-like PCBs is of greater importance. comparison of exposure in the Netherlands with the recommended exposure limits. Humans. Most adults in the Netherlands are exposed to approximately 2 picogrammes of toxic equivalents of dioxin-like substances per kilogramme of body weight per day. In general, it may be stated that in excess of 90% of human exposure to PCDDs, PCDFs and dioxin-like PCBs derives from the consumption of animal fats, of which 50% are contained in milk and milk products. Infants are exposed to these substances before birth as well as through the maternal milk. Their exposure through the maternal milk, expressed per kilogramme of body weight, may thus be substantially higher than that of adults. These exposure figures may be compared to the recommended exposure limit proposed by the Committee. This leads to the conclusion that the possibility that the ingestion of dioxin-like compounds causes adverse health effects in the Dutch population cannot be excluded with reasonable certainty. The Committee believes that it is supported in this conclusion by (Dutch Experts, 1996) (citation incomplete)
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