Acute and Chronic Dioxin Poisoning.

Acute and Chronic Dioxin Poisoning.
Risks to live in an industrialized world. Acute and Chronic Dioxin Poisoning. 16/04/2017 janna koppe

Acute Dioxin Toxicity Seveso (1976) Yusho and Yucheng (1968 and 1978)
Two Austrian secretaries (1997) Yushchenko (2004) High levels of dioxin are found after accidents or unintentional poisoning. In the first three accidents (Seveso, Yusho and Yucheng ) children and pregnant women are involved. The last two are cases of intentional poisoning in adults. 16/04/2017 janna koppe

Acute dioxin poisoning
Severe pure 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Intoxication resulting in chloracne. Picture from internet: Yushchenko autumn 2004, before and after. 16/04/2017 janna koppe

Acute Dioxin Toxicity Clinical Effects Laboratory Effects
In the folllowing slides clinical and laboratory effects are described of acute and/or severe dioxin poisoning. 16/04/2017 janna koppe

Seveso 1976 a few days after. On Saturday 10 July 1976, a major chemical accident occurs in the ICMESA ( Industrie Chimique Meda Società) plant producing 2,4,5 trichlorophenol (TCP) used for the chemical synthesis of herbicides. Since 1963 the plant was owned by ROCHE. About 3000 kg of a mixture of several different pollutants were emissed in the air containing 300 gram to 130 kg dioxin. Three days later it was learned that small animals had died and on July 14 the first signs of skin inflammation occurred in children. Prof. Alvo Cavallaro, being a chemical expert in public health in Milan recognized immediately the danger. The cloud covered Seveso and the region South-East to the plant. The picture is of a boy (Dr. P. Bertazzi) intoxicated with dioxin by dermal contact and through oral exposure.

Exposure routes of humans after the Seveso accident.
Absorption from dermal contact with soil Inhalation of contaminated dust Contribution of drinkable water Ingestion of vegetables grown in home gardens Consumption of animal products (chickens and rabbits) from the area Casual ingestion of soil 16/04/2017 janna koppe

CLINICAL EFFECTS Chloracne Nausea Vomiting Epigastric pain Appetite loss Weight loss Dermal contact but also ingestion of dioxins results in chloracne. Soon after the incidence (4 days) children got signs of skin inflammation. After 1-2 months trhe typical chloracne appears. Chloracne is very itchy and covers the whole body including the genitals. 16/04/2017 janna koppe

Abnormal liver function tests in Seveso children: increase in γ-glutamyltransferase (GGT) Alanine aminotransferase (ALT) In induced abortions in the period the incidence of aberrant cytogenetic findings was increased as was the number of miscarriages in general. In the period after the Seveso accident many women induced abortions being afraid of a congenitally malformed baby, but also the number of miscarriages in general was increased as is also seen in a hot spot of dioxin contamination in Chapaevsk in Russia. References :Tenchini M. et al: A comparative cytogenetic study on cases of induced abortions in TCDD-exposed and non-exposed women. Environ Mutagen 5:73-85 (1983). Revich B et al. Dioxin exposure and public health in Chapaevsk, Russia. Chemosphere 43: (2001). 16/04/2017 janna koppe

Follow-up Seveso Sex, distance from the accident site and meat consumption were significantly associated with an increased TCDD concentration. Abnormal sex ratio (more girls) in relation to paternal exposure. TCDD- concentration in breastmilk after 25 years still twice as high. Increase in all cancers (rectum, lympho-hemopoietic, myeloid, thyroid gland and pleura) In women in Seveso the concentration of TCDD is higher than in man. Births showed an abnormal sex ratio(more girls than boys) and is related to the dose the father was exposed to and his age. After 25 years pure Tetra-CDD is still increased in breastmilk of women, who as children were exposed to dioxin. Other organohalogen compounds and other dioxin congeners are lower than controls and it is supposed that the activation of Cyt. P450 1 A1 plays a role. Ref:Weiss J, Zetterström R. Concentrations of dioxins and other organochlorines (PCBs,DDTs,HCHs) in human milk from Seveso, Milan and a Lombardian rural area in Italy: a study performed 25 years after the heavy dioxin exposure in Seveso. Acta Paed 92: (2003). The increase in rectal cancer is significant, and this is in agreement with a rare observation of an ano-rectal cancer in an 11-year old boy exposed in Times Beach where he lived from In 1982 a widespread contamination of the soil with dioxins was found in Times Beach Missouri due to spraying of unpaved roads with oil containing waste products (TCDD) of an hexachlorophene factory.Ano-rectal cancer at this young age is very rare ( 1 in 10 million). Ref:Pratt CB, George SL, O'Connor D, Hoffman RE. Adolescent colorectal cancer and dioxin exposure. Lancet 2:803 (1987). 16/04/2017 janna koppe

SEX RATIO after SEVESO Sex ratio Unexposed 271 80 0.557 0.438 81 0.506
Fathers concentration Number children Sex ratio Unexposed 271 80 0.557 0.438 81 0.506 0.469 0.400 0.383 It is evident, that in relation to the levels of exposure the sex ratio is changing in the direction of more girls. Ref: Mocarelli P, gertroux P.M., Ferrari E., Patterson D.G., Kieszak S.M., Brambilla P., Vincoli N., Signorini S., Tramacere P, Carreri V., . Paternal concentrations of dioxin and sex ratio of offspring. Lancet 355: (2000). The change in sex ratio is related to the dose the father was exposed to and the age when the father was exposed, under 19 years old. 16/04/2017 janna koppe

Acute Dioxin Poisoning
Coca-cola coloured baby stillborn after YUSHO Placental transfer of PCBs and Furans (1968) In Yusho (Japan 1968) and Yucheng (Taiwan 1978) a poisoning of about 2000 people took place, because of consumption of rice-oil contaminated with PCBs and Furans. There was a leakage of PCBs from the heating system. The poisoning resulted in stillbirth’s and growth retarded babies.The slide shows a coca-cola coloured, severely growth retarded stillborn baby. Characteristic in the babies born alive were prenatal teeth, dysmorfic nails like in the hydantoïn syndrome and a sharp increase in severe respiratory diseases soon after birth with a death rate of 25 %. At follow-up a lower IQ was found and either a timid introvert behaviour or more agression. References: Rogan W.J. et al: Congenital poisoning by polychlorinated biphenyls and their contaminants in Taiwan. Science 241: (1988). Guo Y-L.et al. Yucheng: health effects of prenatal exposure to polychlorinated biphenyls and dibenzofurans. Int Arch Occup Environ Health 77: (2004). Chen YC, Guo YL, Hsu CC, Rogan WJ. Cognitive development of Yu-Cheng ("oil disease") children prenatally exposed to heat-degraded PCBs. JAMA 268: (1992). 16/04/2017 janna koppe

Acute Dioxin Poisoning Two secretaries in Austria 1997
Secretary nr. 1, 30 years old TCDD-level: pg/g fat in blood Intake: 1,5 mg dioxin Soon (few days) after moving in a new office in autumn 1997 : centro-facial chloracne and The secretaries worked in a new building where in another room in a fume cupboard dioxin was found. Dioxin might have been prepared there and then put in the coffee of the secretaries.The level of pure TCDD was very high, respectively Toxic Equivalents Dioxin (TEQ)pg/g fat in blood and TEQ dioxin pg/g fat in blood. Background levels in Europe are on the moment of all dioxins together expressed in toxic equivalents: 20 TEQ dioxin pg /g milkfat. Pure TCDD is the standard of one toxic equivalent. Both secretaries were poisoned with pure TCDD. Ref: Geusau et al: EHP vol 109 nr 8 p 16/04/2017 janna koppe

Secretary nr 1: Epigastric pain, gastritis, nausea Chloracne auricular area, eyelids, genital region, limbs and trunk affected by hundreds of cysts and comedones, Palmoplanar keratoderma Secundary amenorrhoea 16/04/2017 janna koppe

Secretary nr. 1 Ref: Geusau et al: EHP vol 109 nr 8 p 16/04/2017 janna koppe

Acute dioxin Poisoning
Laboratory effects in secr. 1 : Anemia, normochromic, normocytic Trombocytopenia Leucocytosis Natural killer cells slightly lower Triglycerides (7x increased) Liver tests slightly abnormal TSH normal, FT4: normal Secretary nr.1 was the most severely poisoned.(level pg/g fat in blood) Remarkably her thyroïd hormone levels were normal contrary to secretary nr.2 who was much less poisoned (level pg/g fat in blood). Hematologic and liver abnormalities reflect the toxic effect in bone marrow and the liver and are probably mediated by a disrupted heme synthesis. Ref: 1. Sassa S., Kappas A. The Porphyrias. In: Hematology in Infancy and Childhood (Nathan David G., Oski Frank A., eds).W.B.Saunders Company,1993; 2. Sassa S., De Verneuil H., Kappas A. Inhibition of Uroporphyrinogen Decarboxylase Activity in Polyhalogenated Aromatic Hydrocarbon Poisoning. In: Biological Mechanisms of Dioxin Action1984; 16/04/2017 janna koppe

Secretary nr.2: 27 years old TCDD-level : pg/g fat in blood, Intake: 0,4 mg dioxin Gastro-intestinal symptoms during several months since autumn 1997 Not so severe chloracne on the cheeks 16/04/2017 janna koppe

Laboratory effects in nr.2 Marginally elevated cholesterol Triglycerides increased 2x Anemia Trombocytopenia Leukocytosis NK cells lower TSH increased, FT4 normal The increase in TSH (Thyroid Stimulating Hormone) at lower levels of dioxins indicates a problem in the pituitary indicating a thyroxin resistence. A status of thyroxin resistence is created resulting in an intracellular hypothyroïdism, what is compensated with help of a higher thyroid hormone stimulating level. The leukocytosis is probably based on the inflammation of the skin due to acneïform pustules. The scales of the skin contain dioxin, so part of the dioxin is excreted directly by the skin, this explains the much shorter half life (230 days) than is normally found after exposure to small amounts of dioxins for instance through breastfeeding (7years). Ref: Geusau A, Schmaldienst S., Derfler K., Pápke O., Abraham K. Severe 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) intoxication:kinetics and trials to enhance elimination in two patients. Arch Toxicol 76: (2002). 16/04/2017 janna koppe

Acute dioxin poisoning Two year Follow-up of both secretaries
Nr 1: Severe chloracne after one year on the back of the trunk Big problems with chloracne in the face with inflammation Depressed Nr 2: Chloracne disappeared within one year year. 16/04/2017 janna koppe

Back of secretary nr.1 shortly after (c) and one year after the intoxication (d)
16/04/2017 janna koppe

Secr. 1 more chloracne, more abnormal hematological effects more abnormal lipid spectrum than nr. 2 no effect on TSH-level Secr. 2 less chloracne , less abnormal hematological effects less abnormal lipid spectrum effect on TSH-level (increase) 16/04/2017 janna koppe

Bone marrow Anemia Trombocytopenia, NK cells decreased Lipid spectrum Triglycerides increased Cholesterol increased The two secretaries have both signs of intoxication of bone marrow and liver, besides the severe chloracne. The effect on lipid metabolism is striking and also known from the studies in American veterans that were involved in the Vietnam war. Ref: Michalek J.E., Akhtar F.Z., Ketchum N.S., Jackson W.G. The Air Force Health Study: A summary of results. Organohalogen Compounds 54: (2001). Barrett D.H., Morris R.D., Akhtar F.Z., Michalek DB. Serum TCDD and cognitive functioning in veterans of operation ranch hand. Organohalogen Compounds 53: (2001). 16/04/2017 janna koppe

Acute Dioxin Poisoning, follow-up
Chloracne in YUSHO-patient a:shortly after the incident b: after 25 years 16/04/2017 janna koppe

Acute and Chronic Dioxin Poisoning
Trombocytopenia characteristic for dioxin poisoning BASF workers 1953 Japanese workers Two secretaries 4. Dutch children perinatally exposed to background levels In dioxin exposure a characteristic laboratory sign is the trombocytopenia. Together with anemia this might indicate an effect on stem cell level, with the formation of trombocytes being the most susceptible.The references of the four groups were measurements were made are given. Ref: Zober A. et al:Occup Environ Med (1994) Ott et al: Chemosphere 29: (1994) (BASF workers) Watanabe et al: Organohalogen Compounds 53 pp (2001) (Japan) Geusau et al:EHP 109 pp865-69 (Austria) Ten Tusscher et al: EHP vol. 111 pp (2003) (Netherlands) The effect on the trombocytes might be explained by an accumulation of delta-amino laevulinic acid, a molecule formed in the beginning of the heme synthesis; this molecule directs the development of the progenitor cell in the bone marrow in the direction of erythroblasts and away from megakaryocytes. For references on the heme synthesis see ppt 15. 16/04/2017 janna koppe

Acute Dioxin Poisoning In the Long Run
Chloracne improves during 25 years More cancer and 8 years earlier. More diabetes and earlier in life. More hypertension. More miscarriages, prematurity, congenital malformations: congenital hydrocephalus and renal agenesis, and altered sex ratio. More auto-antibodies to different tissues. Earlier decline in cognitive functions. In Russia there are two hot spots, one in Chapaevsk because of a factory producing lindane, an organohalogen compound, contaminated with dioxins and one in Bashkortostan a plant producing 2,4,5-T. The data mentioned in this slide on cancer and reproduction are described in these two hot spots, see Karamova and Revich. Mocarelli describes the effect on the sex ratio, while Michalek describes abnormalities (diabetes, hypertension, lipid spectrum disorders and earlier decline in cognitive functions) in Vietnam veterans. References: Karamova et al: Organohalogen Compounds 52:222-5 (2001) Revich et al:Chemosphere 43: (2001) Mocarelli et al: Lancet 355: (2000) Michalek et al: Organohalogen Compounds (2001) 16/04/2017 janna koppe

Therapy There is no effective therapy. So primary prevention is warranted. Acne therapy with isotretinoin creme may help to treat chloracne Olestra, a resin that absorbs fat in the intestines, interferes with the entero-hepatic cycle and helps removing dioxin-molecules that are excreted in the gall Antioxidants like vitamin C and vegetables high in antioxidants, like broccoli, olive oil, berries, tea, grapes, beats and green vegetables high in chlorophyl. Lactation and liposuction are other possibilities to remove dioxins. 16/04/2017 janna koppe

Conclusion Clinical signs: chloracne, nausea and vomiting, gastro-intestinal effects.Weight loss. Laboratory signs: anemia, trombocytopenia, leukocytosis, increased liver enzymes, dyslipidaemia,TSH increased (not at high dose), NK cells decreased. 16/04/2017 janna koppe

Chronic Dioxin poisoning
Background levels of dioxins are levels found in human milk in non-contaminated areas. In Europe background levels of dioxins were and are a problem. Dioxins are a collective of dioxins and furans and dioxinlike PCBs, expressed as Toxic Equivalent Quantities (TEQ’s). Dioxins, a term often referred to polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) belong to the group of Polyhalogenated-Aromatic- Hydrocarbons (PAH,s). They are lipophilic and can be persistent and bioaccumulating.There are 75 PCDDs and 135 PCDFs, but not all are persistent. In animals higher up in the food chain like cows and human beings those with a chlorine atom at the 2,3,7,8 place are most persistent and toxic. Polychlorinated biphenyls (PCBs) are also a member of the PAH-family. Planar PCBs resemble dioxins and have chlorine atoms at the meta and para position of the biphenyl ring structure. Mono-ortho PCBs have one chlorine atom on the ortho position. They have an effect as dioxins and got because of that also a TEF-value and are now included in a Total TEQ of dioxin-activity. Di-ortho PCBS, the non-dioxinlike ones, have two chlorine atoms in the ortho position.They are also toxic, but other receptors are involved than the Ah-receptor, through which their toxicity is effected. 16/04/2017 janna koppe

Incineration of municipal waste (79% Netherlands)
Chronic Dioxin Poisoning Background concentrations are levels in human milk in non-contaminated areas caused by: Incineration of municipal waste (79% Netherlands) By-products of chlorinated phenol production, Other waste incineration, Metal smelting, Traffic In the Netherlands 79 % of the dioxin emission was caused by municipal incinerators in 1991.The levels in breastmilk decreased with 50 % in 1998 since 1990, after the measures to reduce the emission of dioxins from incinerators in Western Europe. 16/04/2017 janna koppe

Chronic toxicity of dioxins.
Thyroid Hormone Disruptors, Estrogen/Androgen Disruptors, Direct effects on cells. Effects on thyroid metabolism are found in babies in the perinatal period. However negative effects on brain development might be intermediated by the thyroid hormone status in the mother. The first 3 and most of the 4,5 and 6th month of pregnancy the baby is depending on the T4 supply of the mother. Any disturbance in her levels and especially if she has developed auto-antibodies against her thyroid gland the baby can be jeopardized. The slight abnormalities found in the thyroid hormone metabolism around birth in the baby are based on the high need for T4 in that period, at least 5 times more than ever in his life after this period. Ref:Pluim HJ, Koppe JG, Olie K, Vd Slikke JW, Kok JH, Vulsma T, Van Tijn D, de Vijlder JJ. Effects of dioxins on thyroid function in newborn babies. Lancet 339:1303 (1992). And the T4 levels normalize in the first and second year of life. Ref:ten Tusscher G.W., Koppe J.G. Perinatal dioxin exposure and later effects-a review. Chemosphere 54: (2004). Effects on Estrogen/Androgen hormone levels in the perinatal period are not measured in human babies, but lowering of testosteron levels can be hypothesized, because of the enzyme inducing capacity of both dioxins and PCBs that work synergistically in higher, but still low concentrations. Ref:Crofton K.M., Craft E.S., Hedge J.M., Gennings C., Simmons J.E., Carchman R.A., Carter Jr.W.H., DeVito M.J. Thyroid-Hormone-Disrupting Chemicals: Evidence for Dose-dependent Additivity or Synergism. Environ Health Perspect 113: (2005). Remarkebly is the finding by Vreugdenhill on more female play behaviour, indicating an effect on the sexual development of the brain. Ref:Vreugdenhil H.J., Slijper F.M., Mulder P.G., Weisglas-Kuperus N. Effects of perinatal exposure to PCBS and dioxins on play behaviour in Dutch children at school age. Environ Health Perspect 110:A593-A598 (2002). In animals a direct effect on braincells are described as is a negative effect on the dopamine transporter. Ref: Kakeyama M, Tohyama C. Developmental neurotoxicity of dioxin and its related compounds. Ind Health 41: (2003). 16/04/2017 janna koppe

Chronic toxicity of dioxins. Effects in humans.
Liver function, Brain function, Adipose tissue, Lung function, Puberty. Bone marrow, cancer Longer follow-up is needed for reproductive effects. Transient influence of dioxins and PCBS on liver function tests are found shortly after birth in breastfed infants. Ref: Pluim HJ, Koppe JG, Olie K, van der Slikke JW, Slot PC, van Boxtel CJ. Clinical laboratory manifestations of exposure to background levels of dioxins in the perinatal period. Acta Paediatr 83: (1994). Effects on brain function both on cognitive function like an IQ, but also on neurofysiologic parameters is found in the Netherlands in relation to background levels of dioxins and PCBs in the years 1990/1991. Ref:Patandin S, Lanting C.I., Mulder P.G., Boersma E.R., Sauer P.J., Weisgla-Kuperus N. Effects of environmental exposure to polychlorinated biphenyls and dioxins on cognitive abilities in Dutch children at 42 months of age. J Pediatr 134:33-41 (1999). Vreugdenhil H.J., Van Zanten G.A., Brocaar M.P., Mulder P.G., Weisglas-Kuperus N. Prenatal exposure to polychlorinated biphenyls and breastfeeding: opposing effects on auditory P300 latencies in 9-year-old Dutch children. Dev Med and Child Neurology 46 (6): (2004). Both lungfunction and a delay in the development of the breasts in girls are found at follow-up. Both seem to be related to a toxic effect on growth in utero, since both are related with prenatal exposure to dioxins.The effect on the lung is an obstruction measured by an increase in the Fe V1, the amount of air exhaled in one second. Ref:tenTusscher G.W., Weerdt J.de, Roos C.M., Griffioen R.W., De Jongh F.H., Westra M., Slikke J.W.van der, Oosting J., Olie K., Koppe J.G. Decreased lung function associated with perinatal exposure to Dutch background levels of dioxins. Acta Paediatr 90: (2001). The delay in breast development found in Dutch girls is in agreement with animal studies. Ref:Leijs M.M., tenTusscher G.W., Olie K., de Voogt P., Vulsma, T., van Aalderen W.M.C., Westra M., and Koppe J.G. Preliminary results of a cohort study on the influence of perinatal and current dioxin exposure on pubertal growth and development. Congres-child health and the enviornment:results from EU Framework 5 PINCHE, Children Genonetwork and Plutocracy Nov. Brussels Ref Type: abstract Fenton S.E., Hamm J.T., Birnbaum L.S., Youngblood G.L. Persistent abnormalities in the rat mammary gland following gestational and lactational exposure to 2,3,7,8 tetrachlorodibenzo -p-dioxin. (TCDD). Toxicol Sci 67:63-74 (2002). Effects on bone marrow are described in the Dutch studies f.i. Effects on the number of blood platelets and immunologic parameters. Ref: ten Tusscher G.W., Steerenberg P.A., van Loveren H., Vos J.G., von dem Borne A.E.G.K.+, Westra M., van der Slikke J.W., Olie K., Pluim H.J., Koppe J.G. Persistent Hematologic and Immunologic disturbances in 8-year-Old Dutch children Associated with Perinatal Dioxin Exposure. Environ Health Perspect 111: (2003). Weisglas-Kuperus N, Patandin S, Berbers GA, Sas TC, Mulder PG, Sauer PJ, Hooijkaas H. Immunologic effects of background exposure to polychlorinated biphenyls and dioxins in Dutch preschool children. Environ Health Perspect 108 : (2000). 16/04/2017 janna koppe

Chronic Dioxin Poisoning
In the Amsterdam-Zaandam region in the Netherlands a prospective study was started to effects of background levels of dioxins in the perinatal period in the years In the following slides a negative effect on neurofysiologic parameters is described. 16/04/2017 janna koppe

Characteristics of subjects. Amsterdam study started in 1987/1991 Follow-up: 41 healthy 7-12 year old children optimal pregnancies, single births. Dioxin-levels ( I-TEQ dioxin): prenatal exposure ng postnatal exposure ng 16/04/2017 janna koppe

MEG/EEG methods . Cognitive functioning was assessed with help of a visual oddball paradigm. The subject has the task to count the times the oddball is seen, during a continuous presentation of a visual stimulus. ( about 60 times during a session) Strongly associated with N200 (passive attention) and P300 (active attention), subdivided in P3a and P3b. N200 and P3b were analysed. 16/04/2017 janna koppe

Results The latencies of the N 200 and P3b component (pooled EEG- and MEG data) were significantly prolonged (p-value: 0.002) and the amplitude was decreased (p-value: 0.01) in relation to perinatal dioxin exposure 16/04/2017 janna koppe

Acute and Chronic Dioxin Poisoning
Author: Janna G. Koppe CHEST-project. Leaders: Peter van den Hazel Moniek Zuurbier 16/04/2017 janna koppe

Acute and Chronic Dioxin Poisoning.

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