A distinct four-value blood signature of pyrexia under combination therapy of malignant melanoma with dabrafenib and trametinib evidenced by an algorithm-defined pyrexia score.

Pyrexia is a frequent adverse event of BRAF/MEK-inhibitor combination therapy in patients with metastasized malignant melanoma (MM). The study's objective was to identify laboratory changes which might correlate with the appearance of pyrexia. Initially, data of 38 MM patients treated with dabrafenib plus trametinib, of which 14 patients developed pyrexia, were analysed retrospectively. Graphical visualization of time series of laboratory values suggested that a rise in C-reactive-protein, in parallel with a fall of leukocytes and thrombocytes, were indicative of pyrexia. Additionally, statistical analysis showed a significant correlation between lactate dehydrogenase (LDH) and pyrexia. An algorithm based on these observations was designed using a deductive and heuristic approach in order to calculate a pyrexia score (PS) for each laboratory assessment in treated patients. A second independent data set of 28 MM patients, 8 with pyrexia, was used for the validation of the algorithm. PS based on the four parameters CRP, LDH, leukocyte and thrombocyte numbers, were statistically significantly higher in pyrexia patients, differentiated between groups (F = 20.8; p = <0.0001) and showed a significant predictive value for the diagnosis of pyrexia (F = 6.24; p = 0.013). We provide first evidence that pyrexia in patients treated with BRAF/MEK-blockade can be identified by an algorithm that calculates a score.

Dealing with Corticosteroid and High-Dose Cyclosporine Therapy in a Pyoderma Gangrenosum Patient Contracting a COVID-19 Infection.

Pyoderma gangrenosum (PG) is a rare and chronic neutrophil inflammation belonging to the spectrum of autoinflammatory disorders. Immunosuppressive therapy is the cornerstone of successful treatment. However, due to the global COVID-19 pandemic, physicians struggle with therapeutic strategies during infection. This paper describes the case of a 58-year-old patient with a very painful, rapidly increasing wound on his right foot, which was diagnosed as pyoderma gangrenosum. Five weeks after the initial treatment with high-dose immunosuppressives (combination therapy with cyclosporine A and systemic methylprednisolone), he became infected with COVID-19. Reduction in the immunosuppressive dosage proved effective, as the patient recovered from COVID-19 without any complication and showed rapid wound healing.

Cutaneous Malignancies in Tattoos, a Case Series of Six Patients.

BACKGROUND: A variety of side effects following the tattooing of the skin were reported over the years. Analytical studies showed that some tattoo inks contain harmful compounds. METHODS: We presented six patient cases with cutaneous malignancies in tattooed skin and performed an extensive literature research. RESULTS: Two patients with black ink tattoos that were diagnosed with malignant melanoma raises the number of described cases to 36 patients. One of the patients developed an immunologic reaction limited to the tattoo area after treatment with a targeted immune therapy. In the other patient, the malignancy (malignant melanoma) was fatal. Basal cell carcinoma was seen in four patients with tattoos containing varying ink colors (black, green, red). This increased the number of described patient cases to 18. Although some ink components and their cleavage products have carcinogenic properties, epidemiological evidence for a causative correlation fails. Further epidemiologic studies on tattoos and malignancies, as well as on the appearance of naevi in tattoos, are necessary. Determining the type of mutation might be helpful to separate sun-induced tumors from skin cancers due to other pathogenic mechanisms.

Upregulation of CCL7, CCL20, CXCL2, IL-1ß, IL-6 and MMP-9 in Skin Samples of PCB Exposed Individuals-A Preliminary Study.

Polychlorinated biphenyls (PCBs) are well known immunotoxic and carcinogenic compounds. Although cutaneous symptoms are the hallmark of exposure to these compounds, exact pathophysiologic mechanisms are not well understood. We took skin biopsies from moderately high PCB exposed workers (n = 25) after an informed consent and investigated the expression of immunological markers such as CCL-7, CCL-20, CXCL2, IL-1ß and IL-6, as well as the matrix metalloproteinase MMP-9, EPGN and NRF2 by RT-qPCR, and compared expression levels with plasma PCB levels. Statistical analyses showed a significant correlation between CCL-20, CXCL2, IL-6, IL-1ß, CCL-7 and MMP-9 and PCB serum levels. EPGN and NRF2 were not correlated to PCB levels in the blood. We found a significant correlation of genes involved in autoimmune, auto-inflammatory and carcinogenesis in skin samples of PCB exposed individuals with elevated plasma PCB levels. Confirmation of these findings needs to be performed in bigger study groups and larger gen-sets, including multiple housekeeping genes. Further study needs to be performed to see whether a chronical exposure to these and similar compounds can cause higher incidence of malignancies and inflammatory disease.

Correlative Monitoring of Immune Activation and Tissue Damage in Malignant Melanoma-An Algorithm for Identification of Tolerance Breakage During Immune Checkpoint Inhibitor Therapy of Cancer.

We describe an innovative approach for identification of tolerance breakage during immune checkpoint inhibitor therapy in malignant melanoma. Checkpoint inhibitor therapy enhances the immunologic clearance of cancer by suppressing pathways which induce immune suppression and tolerance. We posit that by analyzing temporal correlations of key markers of immune activation and tissue damage it would be possible to detect the onset of anticancer immune reaction as well as of immunologic adverse effects which might become crucial for optimization as well as safety of immune checkpoint inhibitor treatment. We analyzed time courses of routine laboratory values of serum tumor markers as well as of markers of immune activation in 17 patients with metastasized malignant melanoma receiving checkpoint inhibition and weekly laboratory controls. A parallel serum level increase of interleukin-6 and the tumor marker S100B could be identified in 13 patients, suggesting that the onset of tolerance breakage under checkpoint inhibition may be identified and measured. Immune-related adverse events in the patients were also accompanied by a peak of IL-6. In six patients, the onset of a putative anticancer immune reaction and the beginning of immunologic adverse events occurred in the same treatment cycle; in six patients the immunologic adverse reactions took place in separate cycles.

Altered Gene Expression in Dioxin-Like and Non-Dioxin-Like PCB Exposed Peripheral Blood Mononuclear Cells.

Polychlorinated biphenyls (PCBs) are well known carcinogenic persistent environmental pollutants and endocrine disruptors. Our aim was to identify the possible dysregulation of genes in PCB exposed peripheral blood mononuclear cells (PBMCs) in order to give more insight into the differential pathophysiological effects of PCB congeners and mixtures, with an emphasis on immunological effects and oxidative stress. The PBMCs of a healthy volunteer (male, 56 years old) were exposed to a mixture of dioxin-like (DL)-PCBs (PCB 77, 81, 105, 114, 118, 123, 126, 156, 157, 167, 169, and 189, 250 µg/L resp.) or non-dioxin-like (NDL)-PCBs (PCB 28, 52, 101, 138, 153, 180, 250 µg/L resp.) or single PCB congener (no.28, 138, 153, 180, 250 µg/L resp.). After an incubation period of 24 h, a microarray gene expression screening was performed, and the results were compared to gene expression in control samples (PBMCs treated with the vehicle iso-octane). Treatment of PBMCs with the DL-PCB mixture resulted in the largest number of differentially regulated genes (181 upregulated genes >2-fold, 173 downregulated >2-fold). Treatment with the NDL-PCB mix resulted in 32 upregulated genes >2-fold and 12 downregulated genes >2-fold. A gene set enrichment analysis (GSEA) on DL-PCB treated PBMCs resulted in an upregulation of 125 gene sets and a downregulation of 76 gene sets. Predominantly downregulated gene sets were involved in immunological pathways (such as response to virus, innate immune response, defense response). An upregulation of pathways related to oxidative stress could be observed for all PCB congeners except PCB-28; the latter congener dysregulated the least number of genes. Our experiment augments the information known about immunological and cellular stress responses following DL- as well as NDL-PCB exposure and provides new information on PCB 28. Further studies should be performed to evaluate how disruption of these pathways contributes to the development of autoimmune diseases and cancer.

Expression of CYP1A1, CYP1B1 and IL-1ß in PBMCs and skin samples of PCB exposed individuals.

Polychlorinated biphenyls (PCBs) are well- known man-made persistent environmental pollutants and endocrine disruptors. As a result of mass production in the past, background levels of these compounds can be measured in human blood worldwide. In 2010 high internal levels of PCBs were discovered in workers of a transformer-recycling company in Germany. Our aim was to measure, whether the expression of CYP1A1, CYP1B1, and IL-1ß is dysregulated in peripheral blood mononuclear cells (PBMCs) of the exposed individuals (n = max 308). Further, we measured the regulation of CYP1A1, CYP1B1, AHRR (aromatic hydrocarbon receptor repressor) and IL-1ß in skin samples of 25 workers with elevated plasma PCB levels using quantitative PCR (q-RT-PCR). We found a significant correlation between the regulation of IL-1ß in skin samples and lipid adjusted PCB levels. In the PBMCs, the expression levels of CYP1A1, CYP1B1 and IL-1ß decreased over time with decreasing PCB plasma levels. The upregulation of the cytokine IL-1ß in exposed individuals with higher PCB plasma levels warrants further investigation in order to examine its role in the pathophysiology of autoimmune disorders and tumor promotion.

Exposure to Environmental Contaminants and Lung Function in Adolescents-Is There a Link?

Dioxins (polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDF)), polychlorinated biphenyls (PCBs), and brominated flame retardants (BDEs) are well known toxic environmental contaminants. Their possible role in the incidence of respiratory disease is not yet well understood. Previous studies showed a negative effect on lung function in relation to prenatal and lactational dioxin exposure in pre-pubertal children. Effects of BDE exposure on the lung function have not previously been evaluated. As part of a longitudinal cohort study, the effects of perinatal dioxin (PCDD/F) exposure and serum PCDD/F, dl-PCB, and BDE levels on lung function in adolescents were assessed using spirometry, a body box, and diffusion measurements. Thirty-three children (born between 1986 and 1991) consented to the current follow-up study. Prenatal, lactational, and current dioxin, PCB, and BDE concentrations were determined using GC-MS. No relationship was seen between prenatal and lactational dioxin exposure, nor with current PCB body burden, and lung function. Indications of increasing airway obstruction were seen in relation to increasing current BDE exposure. This is a novel finding and certainly warrants further research.

Hyperpigmentation and higher incidence of cutaneous malignancies in moderate-high PCB- and dioxin exposed individuals.

Polychlorinated biphenyls (PCB) are well known persistent and toxic environmental pollutants. Our aim was to identify effects of moderate-high exposure to dioxin-like (dl) and non-dioxin-like (ndl)-PCBs on the skin in order to provide more insight in the pathophysiological effects of these compounds. We performed a dermatological examination on 92 former workers from a transformer recycling company with known elevated serum PCB and/or dioxin (polychlorinated dibenzo-p-dioxin/polychlorinated dibenzo-p-furan (PCDD/F)) levels. In addition, we performed a skin cancer screening over a period of seven years (2010-2016) on resp. 268, 271, 210, 149, 92, 129 and 79 participants. We found a higher incidence of acne and malignancies of the skin (malignant melanoma, basal cell carcinoma and mycosis fungoides) in the workers compared to normal population. The probability of having hyperpigmentation on the skin was statistically significantly higher in workers with higher sumPCBs- (OR:1.09(1.12-2.17)), dioxin-like (dl)-PCBs- (OR:1.56(1.12-2.17)) and dioxin (PCDD/Fs) (OR:1.09(1.02-1.16)) levels. Age was a confounding factor in this model. Formation of hyperpigmentation could be an indicator for (moderate-high) exposure to toxic compounds like PCBs. The higher incidence of cutaneous malignancies found in the workers might be associated with PCB- and dioxin exposure, warranting further investigation on larger cohorts.

Alterations in the programming of energy metabolism in adolescents with background exposure to dioxins, dl-PCBs and PBDEs.

OBJECTIVES: Dioxins and PCBs are highly toxic and persistent environmental pollutants that are measurable in humans worldwide. These persistent organic pollutants are associated with a higher incidence of diabetes mellitus. We hypothesise that perinatal (background) exposure to industrial pollutants like dioxins also influences body mass development and energy metabolism in later life. STUDY DESIGN: In The Netherlands, the perinatal exposure (prenatal exposure and postnatal lactational intake) to dioxins has been studied prospectively since 1987. Fasting glucose, insulin, HbA1c and leptin were analysed in 33 children of the original cohort of 60. BMI, glucose:insulin and BMI:leptin ratios were calculated. Prenatal exposure, lactational intake and current serum levels of dioxins (PCDD/F), dl-PCBs and PBDE concentrations were determined using (HR)GC-MS. RESULTS: Prenatal dioxin (PCDD/F) exposure was positively correlated to the glucose:insulin ratio (p = 0.024) and negatively correlated to the fasting insulin concentration (p = 0.017) in adolescence. Postnatal lactational PCDD/F intake was also negatively correlated to fasting insulin concentration (p = 0.028). Current serum levels of PCDD/Fs and total TEQ (dl-PCBs+PCDD/Fs) were positively correlated to the fasting serum glucose concentration (p = 0.015 and p = 0.037, respectively).No metabolic effects were seen in association with current serum levels of PBDEs. A positive correlation between the insulin and leptin concentrations (p = 0.034) was observed. No effects were found on leptin levels, BMI:leptin ratio, HbA1c levels or BMI. DISCUSSION/CONCLUSION: This study indicates that prenatal and lactational exposure influences glucose metabolism in adolescents, presumably through a negative effect on insulin secretion by pancreatic beta cells. Additionally, the very low recent background exposure to dioxins in puberty possibly has an effect on the glucose level.

Thyroid hormone metabolism and environmental chemical exposure.

BACKGROUND: Polychlorinated dioxins and -furans (PCDD/Fs) and polychlorinated-biphenyls (PCBs) are environmental toxicants that have been proven to influence thyroid metabolism both in animal studies and in human beings. In recent years polybrominated diphenyl ethers (PBDEs) also have been found to have a negative influence on thyroid hormone metabolism. The lower brominated flame retardants are now banned in the EU, however higher brominated decabromo-diphenyl ether (DBDE) and the brominated flame retardant hexabromocyclododecane (HBCD) are not yet banned. They too can negatively influence thyroid hormone metabolism. An additional brominated flame retardant that is still in use is tetrabromobisphenol-A (TBBPA), which has also been shown to influence thyroid hormone metabolism.Influences of brominated flame retardants, PCDD/F's and dioxin like-PCBs (dl-PCB's) on thyroid hormone metabolism in adolescence in the Netherlands will be presented in this study and determined if there are reasons for concern to human health for these toxins. In the period 1987-1991, a cohort of mother-baby pairs was formed in order to detect abnormalities in relation to dioxin levels in the perinatal period. The study demonstrated that PCDD/Fs were found around the time of birth, suggesting a modulation of the setpoint of thyroid hormone metabolism with a higher 3,3', 5,5'tetrathyroxine (T4) levels and an increased thyroid stimulating hormone (TSH). While the same serum thyroid hormone tests (- TSH and T4) were again normal by 2 years of age and were still normal at 8-12 years, adolescence is a period with extra stress on thyroid hormone metabolism. Therefore we measured serum levels of TSH, T4, 3,3',5- triiodothyronine (T3), free T4 (FT4), antibodies and thyroxine-binding globulin (TBG) in our adolescent cohort. METHODS: Vena puncture was performed to obtain samples for the measurement of thyroid hormone metabolism related parameters and the current serum dioxin (PCDD/Fs), PCB and PBDE levels. RESULTS: The current levels of T3 were positively correlated to BDE-99. A positive trend with FT4 and BDE-99 was also seen, while a positive correlation with T3 and dl-PCB was also seen. No correlation with TBG was seen for any of the contaminants. Neither the prenatal nor the current PCDD/F levels showed a relationship with the thyroid parameters in this relatively small group. CONCLUSION: Once again the thyroid hormone metabolism (an increase in T3) seems to have been influenced by current background levels of common environmental contaminants: dl-PCBs and BDE-99. T3 is a product of target organs and abnormalities might indicate effects on hormone transporters and could cause pathology. While the influence on T3 levels may have been compensated, because the adolescents functioned normal at the time of the study period, it is questionable if this compensation is enough for all organs depending on thyroid hormones.

Effects of dioxins, PCBs, and PBDEs on immunology and hematology in adolescents.

Dioxins and PCBs are environmental pollutants, proven to be immunotoxic. In the period 1987-1991 a cohort of mother-baby pairs was initiated to detect abnormalities in relation to dioxin levels in the mother's milk. At birth and at follow-up at 8-12 years, immunological and hematological effects were seen, prompting us to perform a new follow-up during adolescence. In addition, we assessed the immunological and hematological parameters in relation to current levels of PBDEs and PCBs. In the Netherlands, the pre- and postnatal exposure to dioxins have been studied prospectively since 1987. Venapuncture was performed to assess hematological (Hemoglobin, thrombocytes, thrombopoietin) and immunological (leukocytes, leukocyte differentiation) parameters and the current serum levels of dioxin, dioxinlike (dl)-PCBs and PBDEs. A decrease in the number of polymorphic neutrophils was found in adolescents with higher dl-PCBs in their serum (p = 0.021). No relation with total leukocytes, thrombocytes, hemoglobin, or thrombopoietin levels was seen. Similarly, we found no relation between prenatal, nor current dioxin levels and the hematological and the immunological parameters determined. The SigmaPBDEs were negatively associated with the number of lymphocytes (p = 0.01) and positively associated with the hemoglobin concentration (p = 0.003). These effects on the innate immunity by current levels of dl-PCBs and on the adaptive immunity by PBDEs are disconcerting, especially as the dl-PCB (0.04-7.8 WHOTEQ pg/g lipid, mean: 2.2 WHOTEQ pg/g lipid) and SigmaPBDE levels (mean 14.0 ng/g lipid, including one outlier with a sum of 73.6 ng/g lipid) were not high.

Delayed initiation of breast development in girls with higher prenatal dioxin exposure; a longitudinal cohort study.

OBJECTIVES: While many studies have assessed the health impacts of PCDD/Fs and PCBs on animals and humans, long-term consequences for especially adolescents, have not (yet) been well documented. This is certainly also true for the effects of PBDE exposure. As part of a longitudinal cohort study, now well into its second decade, effects of perinatal and current PCDD/F exposure, as well as current dl-PCB and PBDE exposures, on puberty, were assessed. STUDY DESIGN: Prenatal, lactational and current PCDD/F, dl-PCB and PBDE concentrations were determined using GC-MS. Pubertal development and growth were assessed by means of physical examination and the Tanner scale. 33 Children (born between 1986 and 1991) consented to the current follow-up study. Outcomes were evaluated using linear regression or the non parametric Spearman's correlation coefficient. RESULTS: A delay in initiation of breast development was found in girls (n = 18) with higher prenatal (p = 0.023) and lactational PCDD/F exposure (p = 0.048). The males revealed a negative trend with age at first ejaculation. For other endpoints on puberty and growth (pubic hair, axillary hair, genital stage, length, BMI, testicular volume, menarche) no significant relation was found with any of the measured compounds. DISCUSSION AND CONCLUSION: A relation between prenatal PCDD/F exposure and later initiation of breast development was seen. A Belgian study found a delay in breast development with higher current serum concentrations of dioxin-like compounds. The initiation of puberty is a complex process and it is yet not clear how dioxin-like compounds precisely affect this process prenatally. Further follow-up into adulthood is warranted, in order to detect the possibility of developing malignancies and fertility problems.

Endocrine disruptors and abnormalities of pubertal development.

Onset and development of puberty is regulated by the neuroendocrine system. Population-based studies worldwide have observed secular trends towards earlier puberty development. These changes are apparently caused by environmental factors such as improved socio-economic status, improved health care and nutrition. However, they may also partly result from endocrine-disrupting chemicals in the environment. Epidemiological studies have investigated the relationship between pubertal development and exposure to endocrine-disrupting chemicals (polychlorinated biphenyls, polybrominated biphenyls, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, phthalate esters, furans and the pesticide endosulfan). Associations with both perinatal and postnatal exposure have been reported. Studies in experimental animals support some of these findings and point to differential endocrine regulatory mechanisms linked to pubertal development acting in the perinatal and the pre-pubertal period. Pubertal development is naturally associated with growth and body composition. There is increasing evidence for a link between prenatal development and pubertal onset. In girls born small for gestational age (SGA), pubertal onset and age at menarche often are advanced, especially if there has been an extensive catch-up growth during the first months of life. In utero growth retardation may have multiple causes including exposure to xenobiotic substances as was suggested for some endocrine-disrupting chemicals. An abnormal perinatal environment of children born SGA may alter the endocrine status and the sensitivity of the receptors for endocrine and metabolic signalling that may have effects on maturation of brain and gonads. However, the causal pathways and the molecular mechanisms that may link the pubertal growth pattern of children born SGA, pubertal development and endocrine-disrupting chemicals need further study.

Paediatric environmental health history taking: why bother?

Environmental health history taking is often not part of standard medical history taking for clinical physicians. During recent years attention has been placed on home environments and asthma and allergies, high caloric intake and obesity and type 2 diabetes mellitus, yet environmental health history taking still remains relatively uncharted terrain for the clinical physicians of today. While the reasons for this are certainly varied, ignorance of environmental influences, ignorance of environmental pollutants, politics and prejudices will certainly play a role. We suggest a simple manner of environmental health history taking, and discuss the importance of the subject in our modern-day clinical practice.

Today's epidemics in children: possible relations to environmental pollution and suggested preventive measures.

BACKGROUND: Facts and hypotheses on the relationship between some children's diseases or disorders and external stressors during the developmental stage of a child, both prenatally and postnatally are described in literature. In this paper the following changes in patterns and causes of the main childhood illnesses are summarized and recommendations for actions are made. Prematurity. Intra-uterine growth restriction. Testicular dysgenesis syndrome. Type I and Type II diabetes. Asthma, atopy and hay fever. Autism. Attention deficit hyperactivity disorder (ADHD). Learning disabilities. Cancer. Obesity. Hearing problems. RESULTS: Literature provides a growing amount of information on changing patterns in childhood diseases. CONCLUSIONS: The following recommendations for action are formulated: Immediate research on endocrine disrupters in relation to prematurity. Diabetes: avoid Maillard Compounds in liquid baby food and in food in general: promote breastfeeding. Asthma: avoid exposure to smoking, the use of chemical household products, dioxin and dioxin-like chemicals, and avoid air pollution with high levels of particulate matter, especially around conception, during pregnancy and in the first years of life. Autism: more research on incidence and causes. ADHD and learning disabilities: more research on prevalence and causes. Preventions: 1) preconception counselling to avoid potentially harmful substances; 2) controlling and further lowering levels of polychlorinated biphenyls, lead and methyl mercury. Cancer: promote breastfeeding, carry out research into effects of foetal exposure to internal fission-product radionuclides. Obesity: stop smoking in pregnancy, avoid parental obesity, longer night sleep. Hearing problems: lower noise levels in discothèques, promote the day-evening-night level to avoid noise (longer night sleep).

The effects of PCBs and dioxins on child health.

BACKGROUND/EXPOSURE: Dioxins and PCBs are highly persistent and highly toxic environmental pollutants which at present are derived mainly from waste incineration and food contamination. They are widespread in nature and pollute human food, including breast milk so that basically all children in Europe are exposed to measurable levels. RESULTS/TOXICITY IN CHILDREN: The toxicity of dioxins and PCBs are well described both from animal studies and from a number of human epidemiological studies including several large cohort studies. Especially developmental exposure has been shown to affect endocrine and cognitive systems negatively. Measurable outcomes include reduced IQ and changed behaviour. Foetotoxic effects with reduced birth weight and increased congenital anomalies such as cleft lip have also been described. Exposure to PCBs and dioxins must be considered also in the context of multiple exposure to several toxins simultaneously or sequentially. CONCLUSION/SUGGESTED ACTION: Some measures aimed at reducing exposure to dioxins have been partly successful in that the dioxin content of breast milk is going down. However, further steps to reduce exposure must be taken. We suggest legislative measures for reducing the re-entry of especially PCBs from waste into the environment. Individual pre-conception counselling is recommended in order to reduce developmental exposure and its consequences. Biomonitoring of the substances themselves in breast milk and foods is recommended as well as monitoring possible endocrine effects.

Children's exposure to polybrominated diphenyl ethers.

BACKGROUND: Polybrominated biphenyl ethers (PBDEs), a class of brominated flame retardants, are frequently used in consumer products. PBDEs levels in environmental and human samples have increased in recent decades. Children are exposed to PBDEs through diet, mainly through fish, meat and milk. Total dietary exposure of children in Europe was calculated to be 2-3 ng/kg b.w./day. For nursing infants the main source of PBDE exposure is breast milk; exposure levels are around 15 ng/kg b.w./day. PBDE exposure levels in North America are 10 to a 100 times higher. Because of their persistence and their similarity to polychlorinated biphenyls (PCBs), concern has been raised about the effects of PBDEs on human health. Exposure to penta- and octa-BDE led to learning impairment and impaired motor behaviour in rodents. Exposure to penta-, octa- and also deca-BDE caused effects on thyroid homeostasis in animals. CONCLUSIONS: The EU has banned the production and use of penta- and octa-BDE since 2004; however, exposure will continue during the coming decades. Based upon current toxicological evidence, human exposure to deca-BDEs is not expected to lead to health effects, but data on exposure to deca-BDE and data on toxicity of deca-BDE are scarce. Therefore, monitoring studies and toxicity studies on deca-BDEs and other BDEs should continue.

Exposure to multiple environmental agents and their effect.

INTRODUCTION: All children are exposed to multiple physical, chemical and biological challenges that can result in adverse health effects before and after birth. In this context, the danger of multiple exposures cannot be assessed from a single-chemical approach as used in classical toxicology. AIM: To open up a 'negotiation space' for the problem of multiple exposure to environmental stressors, defined as any physical, chemical or biological entity that can induce an adverse response. In this context, two further questions obtain: to what extent can synergistic risks be assessed, and how far could potential adverse effects be prevented by enhanced regulation? METHODS: A discussion of two general approaches is taken: 1) the investigation of mixtures such as smoking or air pollution without specifying the individual agents, and 2) the investigation of individual substances with a focus on possible interactions in the context of dose to receptor. RESULTS: Although mixtures of compounds can have effects, it may not be possible to ascribe causation to a single compound. Furthermore, cumulative low-dose insult can, in some circumstances, be more toxic than a single high-dose exposure, e.g. endocrine disruptive effects of a combination of PCBs and dioxins which disrupt the thyroid hormone status; this tends to contradict elements of classical toxicology, . These cumulative insults may further combine with heavy metals and can disrupt the heme synthesis. It is possible that groups of pollutants could be used to test their cumulative capacity to multiple stress-susceptible receptor targets as is done in smoking and air pollution. This methodology could be used for further groups of potential pollutants, for example those associated with cleaning products, or cosmetics. Testing individual substances with a focus on interactions means that not only chemicals but also concurrent diseases should be taken into account. We suggest that the enhanced regulation of potential multiple stressors falls into two discrete categories. The first comprises a more precautionary approach (as demonstrated by the banning of chemicals such as some brominated flame retardants in Europe). The second comprises a more 'permissive' liberal approach involving the initial study of an individual compound, and subsequent interrogation of that compound in combination with another (as demonstrated by lowering the carcinogenicity of aflatoxin by vaccination against hepatitis B). CONCLUSIONS: It is necessary to define and study groups of multiple stressors as in US EPA's Framework for Cumulative Risk Assessment (U.S. EPA 2003). Recent increased knowledge of the greater sensitivity of the unborn baby, the infant and the child, has led to general recognition that a higher degree of precaution is now needed in regulating for multiple stressors on the young. The more liberal permissive approach proceeding from established effects of the individual exposures is becoming less acceptable now that we know that there is much we do not understand about chronic effects of stressors during the early development phases. Conflicts over which approach to take may have to be resolved through engagement and negotiation with a wide community of stakeholders. This "community of interest" may include fundamental research scientists, practicing clinical paediatricians, patient groups, and others concerned with the health and wellbeing of infants and children.