The allopurinol hypersensitivity syndrome.

We describe a 61-year-old male patient who was treated with allopurinol and developed fever, a skin rash, eosinophilia and severe renal and liver dysfunction. We discuss the allopurinol hypersensitivity syndrome as a serious complication of the use of allopurinol, and briefly review the aetiology, prevention and treatment modalities.

Missing effects of background dioxin exposure on development of breast-fed infants during the first half year of life.

Fetal exposure to higher levels of PCBs can result in low birth weight and neurological disorders of the newborn. In this study the effects of exposure to the highly toxic dioxins and dibenzofurans, structurally related to PCBs, was investigated in a population of 38 healthy infants. The infants were divided into two groups, according to concentrations of dioxins and dibenzofurans in their mothers milk fat. Neonatal body weight, length, Quetelet index and liver size were determined at different time points during the first half year of life. Additionally neurological development was determined. Comparing these items between the high and low exposure groups did not show any statistically significant differences. The results of this study do not reveal any effect of exposure to background levels of dioxins and dibenzofurans, but in utero exposure to these toxic agents may result in symptoms later in life. Therefore follow-up study of this well defined group will be performed.

Signs of enhanced neuromotor maturation in children due to perinatal load with background levels of dioxins. Follow-up until age 2 years and 7 months.

We investigated psychomotor development (Bayley-test) and neuromotor functioning (Hempel-test) in a group of children with known perinatal load with background levels of dioxins. Bayley-test (n = 32) at 2 years, and additionally investigated growth, medical history, physical condition, TT4, TT4/TBG, TSH, AST and ALT at the age of 2.5 years did not reveal abnormalities, or differences between the high- and the low-exposure group. Although the Hempel-test was normal in all children (n = 31), we found in 22 out of 29 items less suboptimal scores in the high-exposure group; in five items this difference reached significance (p < 0.05). Total-score and subtotal-score (posture of legs and feet excluded) revealed lower "suboptimality-scores" with a wider range in the high-exposure group in comparison to the low-exposure group (total-score p = 0.008 mean 6.7 SD 3.6 and mean 9.3 SD 1.8 respectively and subtotal-score p = 0.06 mean 4.5 SD 2.9 and mean 6.1 SD 1.6 respectively (Mann-Whitney or Wilcoxon Two-Sample Test). Similar signs of enhanced maturation have been described in the tadpole due to low dosis of TCDD. Reflexes were higher (p = 0.02), with a wider range of findings in the high-exposure group. Our hypothesis is that these findings may be due to thyroxine agonistic action of dioxins, which is in accordance with the earlier described signs of relatively high thyroid function in the first 11 weeks of life in this high-exposure group.

Influence of short-term dietary measures on dioxin concentrations in human milk.

Breast-feeding may expose infants to high levels of toxic chlorinated dioxins. To diminish intake of these lipophilic compounds by the baby, two diets were tested for their ability to reduce concentrations of dioxins in human milk. The diets were a low-fat/high- carbohydrate/low-dioxin diet. (about 20% of energy intake derived from fat) and a high fat /low-carbohydrate/low-dioxin diet. These diets were tested in 16 and 18 breast-feeding women, respectively. The test diets were followed for 5 consecutive days in the fourth week after delivery. Milk was sampled before and at the end of the dietary regimen, and dioxin concentrations and fatty acid concentrations were determined. Despite significant influences of these diets on the fatty acid profiles, no significant influence on the dioxin concentrations in breast milk could be found. We conclude that short-term dietary measures will not reduce dioxin concentration in human milk.

Clinical laboratory manifestations of exposure to background levels of dioxins in the perinatal period.

The effects of exposure to low levels of dioxins in infants (intrauterine and via breast milk) were studied. In a group of 35 babies, specially selected, laboratory tests were performed in cord blood and in blood sampled at 7 days and 11 weeks of age. The outcome of these laboratory tests was related to dioxin concentrations in milk fat and cumulative dioxin intake. At 11 weeks of age, alanine aminotransferase and aspartate aminotransferase activities in plasma were significantly related to cumulative dioxin intake. A significant negative relation was found between platelet count and cumulative dioxin intake. The results of this study suggest that exposure to background levels of dioxins, both intrauterine and via breast milk, may have effects in newborns.

Effects of pre- and postnatal exposure to chlorinated dioxins and furans on human neonatal thyroid hormone concentrations.

Animal studies have shown that dioxins influence plasma thyroid hormone concentrations. To investigate the effect of chlorinated dioxins and furans on thyroid hormone concentrations in humans, we studied 38 healthy breast-fed infants. The study population was divided into two groups according to the dioxin concentrations in milk fat of their mothers. Blood samples were taken at birth and at the ages of 1 and 11 weeks. At birth a tendency to higher total thyroxine (tT4) concentrations was found in the high exposure group. At the ages of 1 and 11 weeks the increase of mean tT4 concentrations and tT4/thyroxine-binding globulin ratios in the high exposure group reached significance as compared to the low exposure group. At birth and 1 week after birth, mean thyrotropin (TSH) concentrations were similar in both groups, but at the age of 11 weeks the mean TSH concentrations were significantly higher in the high exposure group. We postulate that the observed plasma tT4 elevation in infants exposed to dioxins before and after birth is the result of an effect on the thyroid hormone regulatory system.

Breast milk, dioxins and the possible effects on the health of newborn infants.

The concentration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the fat of breast milk of 14 Dutch mothers varied from 5.35 to 17.0 ng kg-1 (nanograms per kilogram fat). Expressed as toxic equivalents the concentrations of the 17 different congeners of dioxin and furans in the fat of the breast milk were between 29.85 and 92.88 ng kg-1. These levels are sufficient to induce enzyme formation in the livers of infants. (The acceptable daily intake is 4 pg/kg bodyweight/day). Dioxin induces the same enzyme production in the liver as phenobarbital; therefore, because phenobarbital affects fat-soluble vitamins, such as vitamins D and K, a similar response was anticipated in response to exposure to dioxin. Consequently, one aim of this study was to investigate blood coagulation parameters. We found a statistically significant relationship with the mean concentration of TCDD in the breast milk of mothers whose babies suffered from bleeding problems. This association was not found for 2,3,4,7,8-pentachlorodibenzofuran concentrations, nor for the remaining congeners expressed as toxic equivalents. A simple laboratory test for measuring dioxins and furans is urgently needed.

[Breast feeding, PCBs and dioxins]. / Borstvoeding, PCB's en dioxinen.

In breastmilk of 14 Dutch mothers and 5 Polish mothers the content of dioxins and furans is measured. The study in Dutch mothers is started to relate the level of these xenobiotics to bleeding in the perinatal and late neonatal period. Interference with coagulation is hypothesized in analogon to phenobarbital. A relation is seen between bleeding in four babies and the mean content of 2, 3, 7, 8 TCDD (= tetrachloordibenzodioxin) (P = 0.02) in their breastmilk. This relation however is not found for the content of 2, 3, 4, 7, 8 PnCDF (= pentachloordibenzofuran) or the total amount of toxic equivalents. The fact that the prenatal gradient from mother to baby is different for T4CDD and PnCDF, respectively 2:1 and 10:1, may be an explanation for the dissociation between T4CDD on one side and PnCDF and total amount of toxic equivalents on the other side. Polish breastmilk was significantly lower (about four times) for dioxins and furans than Dutch breastmilk. This means that for these chemicals pollution in Holland is much higher than in Poland.