Lead intoxication in dogs: risk assessment of feeding dogs trimmings of lead-shot game.

BACKGROUND: Expanding lead-based bullets, commonly used for hunting of big game, produce a scattering of lead particles in the carcass around the wound channel. Trimmings around this channel, which are sometimes fed to dogs, may contain lead particles. The aim of this study was to assess potential health effects of feeding dogs such trimmings. RESULTS: Lead ingestion most commonly causes gastrointestinal and neurological clinical signs, although renal, skeletal, haematological, cardiovascular and biochemical effects have also been reported. Experimental data indicate that a daily dose of around 1 mg lead as lead acetate/kg body weight for ten days may be considered as a Lowest Observed Effect Level in dogs. Acute toxicity documentation from the Centers for Disease Control and Prevention indicates 300 mg/kg body weight as the lowest dose of lead acetate causing death in dogs after oral ingestion. Our assessment suggests that dogs fed trimmings of lead-shot game may be affected by the amounts of lead present, and that even deadly exposure could occasionally occur. The intestinal absorption of lead from bullets was assumed to be 10-80 % of that of lead acetate, reflecting both the variability in particle size and uncertainty about the bioavailability of metallic lead in dogs. CONCLUSIONS: Despite data gaps, this study indicates that feeding dogs trimmings of lead-shot game may represent a risk of lead intoxication. More research is needed to assess the exact consequences, if lead-based bullets are still to be used. Meanwhile, we recommend that trimmings close to the wound channel should be made inaccessible to dogs, as well as to other domestic or wild animals.

Prenatal mercury exposure and infant birth weight in the Norwegian Mother and Child Cohort Study.

OBJECTIVE: To examine the association between calculated maternal dietary exposure to Hg in pregnancy and infant birth weight in the Norwegian Mother and Child Cohort Study (MoBa). DESIGN: Exposure was calculated with use of a constructed database of Hg in food items and reported dietary intake during pregnancy. Multivariable regression models were used to explore the association between maternal Hg exposure and infant birth weight, and to model associations with small-for-gestational-age offspring. SETTING: The study is based on data from MoBa. SUBJECTS: The study sample consisted of 62 941 women who answered a validated FFQ which covered the habitual diet during the first five months of pregnancy. RESULTS: Median exposure to Hg was 0·15 µg/kg body weight per week and the contribution from seafood intake was 88 % of total Hg exposure. Women in the highest quintile compared with the lowest quintile of Hg exposure delivered offspring with 34 g lower birth weight (95 % CI -46 g, -22 g) and had an increased risk of giving birth to small-for-gestational-age offspring, adjusted OR = 1·19 (95 % CI 1·08, 1·30). Although seafood intake was positively associated with increased birth weight, stratified analyses showed negative associations between Hg exposure and birth weight within strata of seafood intake. CONCLUSIONS: Although seafood intake in pregnancy is positively associated with birth weight, Hg exposure is negatively associated with birth weight. Seafood consumption during pregnancy should not be avoided, but clarification is needed to identify at what level of Hg exposure this risk might exceed the benefits of seafood.

Mercury exposure in the Norwegian Mother, Father, and Child Cohort Study - measured and predicted blood concentrations and associations with birth weight.

Background: Blood total mercury concentration (BTHg) predominantly contains methyl Hg from seafood, and less inorganic Hg. Measured BTHg is often available only in a small proportion of large cohort study samples. Associations between estimated dietary intake of total Hg (THg) and lower birth weight within strata of maternal seafood intake was previously reported in the Norwegian Mother, Father, and Child Cohort Study (MoBa). However, maternal seafood consumption was associated with increased birth weight, indicating negative confounding by seafood in the association between THg intake and birth weight. Using predicted BTHg as a proxy for measured BTHg, we hypothesized that predicted BTHg would be associated with decreased birth weight. Objectives: To develop and validate a prediction model for BTHg in MoBa and to examine the association between predicted BTHg and birth weight in the MoBa population. Methods: Using linear regression, measured maternal BTHg (n = 1437) was used to build the best fitting model (highest R-squared value). Model validation (n = 1436) was based on correlation and weighted Kappa (Кw). Associations between predicted BTHg in the MoBa population (n = 86,775) or measured BTHg (n = 3590) and birth weight were assessed by multivariate linear regression models. Results: The best fitting model had R-squared = 0.3 and showed strong correlation (r = 0.53, p < 0.001) between predicted and measured BTHg. Cross-classification (quintiles) showed 73 % correctly classified and 3.3 % grossly misclassified, with Кw of 0.37. Measured BTHg was not associated with birth weight. Predicted BTHg was significantly associated with higher birth weight. There were no trends in birth weight with increasing quintiles of measured or predicted BTHg after stratification into high or low seafood consumption. Conclusions: The results indicate that prediction of BTHg did not overcome negative confounding of the association between Hg exposure and birth weight by seafood intake. Furthermore, effect on birth weight of toxicological concern is unexpected in our observed BTHg range.

Recent advances in the risk assessment of melamine and cyanuric acid in animal feed.

Melamine can be present at low levels in food and feed mostly from its legal use as a food contact material in laminates and plastics, as a trace contaminant in nitrogen supplements used in animal feeds, and as a metabolite of the pesticide cyromazine. The mechanism of toxicity of melamine involves dose-dependent formation of crystals with either endogenous uric acid or a structural analogue of melamine, cyanuric acid, in renal tubules resulting in potential acute kidney failure. Co-exposure to melamine and cyanuric acid in livestock, fish, pets and laboratory animals shows higher toxicity compared with melamine or cyanuric acid alone. Evidence for crystal formation between melamine and other structural analogs i.e. ammelide and ammeline is limited. Illegal pet food adulterations with melamine and cyanuric acid and adulteration of milk with melamine resulted in melamine-cyanuric acid crystals, kidney damage and deaths of cats and dogs and melamine-uric acid stones, hospitalisation and deaths of children in China respectively. Following these incidents, the tolerable daily intake for melamine was re-evaluated by the U.S. Food and Drug Administration, the World Health Organisation, and the Scientific Panel on Contaminants in the Food Chain of the European Food Safety Authority (EFSA). This review provides an overview of toxicology, the adulteration incidents and risk assessments for melamine and its structural analogues. Particular focus is given to the recent EFSA risk assessment addressing impacts on animal and human health of background levels of melamine and structural analogues in animal feed. Recent research and future directions are discussed.

Association between gestational levels of toxic metals and essential elements and cerebral palsy in children.

Introduction: Cerebral palsy (CP) is the most common motor disability in childhood, but its causes are only partly known. Early-life exposure to toxic metals and inadequate or excess amounts of essential elements can adversely affect brain and nervous system development. However, little is still known about these as perinatal risk factors for CP. This study aims to investigate the associations between second trimester maternal blood levels of toxic metals, essential elements, and mixtures thereof, with CP diagnoses in children. Methods: In a large, population-based prospective birth cohort (The Norwegian Mother, Father, and Child Cohort Study), children with CP diagnoses were identified through The Norwegian Patient Registry and Cerebral Palsy Registry of Norway. One hundred forty-four children with CP and 1,082 controls were included. The relationship between maternal blood concentrations of five toxic metals and six essential elements and CP diagnoses were investigated using mixture approaches: elastic net with stability selection to identify important metals/elements in the mixture in relation to CP; then logistic regressions of the selected metals/elements to estimate odds ratio (OR) of CP and two-way interactions among metals/elements and with child sex and maternal education. Finally, the joint effects of the mixtures on CP diagnoses were estimated using quantile-based g-computation analyses. Results: The essential elements manganese and copper, as well as the toxic metal Hg, were the most important in relation to CP. Elevated maternal levels of copper (OR = 1.40) and manganese (OR = 1.20) were associated with increased risk of CP, while Hg levels were, counterintuitively, inversely related to CP. Metal/element interactions that were associated with CP were observed, and that sex and maternal education influenced the relationships between metals/elements and CP. In the joint mixture approach no significant association between the mixture of metals/elements and CP (OR = 1.00, 95% CI = [0.67, 1.50]) was identified. Conclusion: Using mixture approaches, elevated levels of copper and manganese measured in maternal blood during the second trimester could be related to increased risk of CP in children. The inverse associations between maternal Hg and CP could reflect Hg as a marker of maternal fish intake and thus nutrients beneficial for foetal brain development.

Intestinal carcinogenesis of two food processing contaminants, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 5-hydroxymethylfurfural, in transgenic FVB min mice expressing human sulfotransferases.

Humans express sulfotransferases (SULTs) of the SULT1A subfamily in many tissues, whilst the single SULT1A gene present in rodents is mainly expressed in liver. The food processing contaminants, 5-hydroxymethylfurfural (HMF) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), are bioactivated by human SULT1A1 and SULT1A2. FVB multiple intestinal neoplasia (Min) mice, which spontaneously develop tumors and flat aberrant crypt foci (ACF) in intestine, were crossed with transgenic FVB mice expressing human SULT1A1 and 1A2 (hSULT) in several tissues, giving rise to wild-type and Min mice with and without hSULT. One-week-old Min mice with or without hSULT were given HMF (375 or 750 mg/kg bw) or saline by gavage three times a week for 11 wk. In another experiment, the F1 generation received subcutaneous injections of 50 mg/kg bw PhIP or saline 1 wk before birth, and 1, 2, and 3 wk after birth. HMF did not affect the formation of tumors, but may have induced some flat ACF (incidence 15-20%) in Min mice with and without hSULT. No control mouse developed any flat ACF. With the limitation that these putative effects were weak, they were unaffected by hSULT expression. The carcinogenic effect of PhIP increased in the presence of hSULT, with a significant increase in both incidence (31-80%) and number of colonic tumors (0.4-1.3 per animal). Thus, intestinal expression of human SULT1A1 and 1A2 might increase the susceptibility to compounds bioactivated via this pathway implying that humans might be more susceptible than conventional rodent models.

Urinary deoxynivalenol as a biomarker of exposure in different age, life stage and dietary practice population groups.

The Fusarium mycotoxin deoxynivalenol (DON) and its modified forms are present in most samples of grain and grain-based products. Due to the widespread presence of DON in these highly consumed food commodities, nearly all individuals are exposed to DON. Previous estimates of the dietary DON intake in Norway indicated that children's dietary intake is close to or exceed the TDI of 1 µg/kg bw/day for the sum of DON and three modified forms. One aim of the current study was to determine whether the concentrations of DON in morning urine differ between population groups like men, women, children, vegetarians, and pregnant women. An additional aim was to compare a set of models for estimating the dietary intake of DON based on urinary DON concentrations and also compare these models with DON-intakes estimated using food consumption data. DON and metabolites were detected in the morning urine from 256 out of 257 individuals and with concentrations in similar range as reported from other countries. Children have higher urinary DON-concentration than adults and elderly. The urinary DON-concentration in pregnant women and vegetarians did not differ from other adults. The estimated intake of DON was higher for children than for other age groups on a body weight basis. The correlations between different models for estimating DON-intake based on urinary concentration as well as based on individual food consumption were good (0.79-0.99), but with some outliers. We conclude that Norwegians are exposed to DON in the same range as reported from other countries and that children have a higher exposure than adults. Furthermore, we conclude that intake estimates based on urinary DON concentration is a useful tool for evaluation of the exposure at population level, but due to outliers, the estimates for individuals are uncertain. There are also uncertainties in intake estimates both from food consumption and from urinary DON concentration, and we could not conclude on which approach provides the most accurate exposure estimate.

Does the food processing contaminant acrylamide cause developmental neurotoxicity? A review and identification of knowledge gaps.

There is a worldwide concern on adverse health effects of dietary exposure to acrylamide (AA) due to its presence in commonly consumed foods. AA is formed when carbohydrate rich foods containing asparagine and reducing sugars are prepared at high temperatures and low moisture conditions. Upon oral intake, AA is rapidly absorbed and distributed to all organs. AA is a known human neurotoxicant that can reach the developing foetus via placental transfer and breast milk. Although adverse neurodevelopmental effects have been observed after prenatal AA exposure in rodents, adverse effects of AA on the developing brain has so far not been studied in humans. However, epidemiological studies indicate that gestational exposure to AA impair foetal growth and AA exposure has been associated with reduced head circumference of the neonate. Thus, there is an urgent need for further research to elucidate whether pre- and perinatal AA exposure in humans might impair neurodevelopment and adversely affect neuronal function postnatally. Here, we review the literature with emphasis on the identification of critical knowledge gaps in relation to neurodevelopmental toxicity of AA and its mode of action and we suggest research strategies to close these gaps to better protect the unborn child.

Patterns and dietary determinants of essential and toxic elements in blood measured in mid-pregnancy: The Norwegian Environmental Biobank.

BACKGROUND: Inadequate stores or intakes of essential minerals in pregnancy, or too high exposure to both toxic and essential elements, can have adverse effects on mother and child. The main aims of this study were to 1) describe the concentrations and patterns of essential and toxic elements measured in maternal whole blood during pregnancy; 2) identify dietary, lifestyle and sociodemographic determinants of element status; and 3) explore the impact of iron deficiency on blood element concentrations. METHODS: This study is based on blood samples collected from 2982 women in gestational week 18 in The Norwegian Mother and Child Cohort study (MoBa) which were analyzed as part of the Norwegian Environmental Biobank. We derived blood element patterns by exploratory factor analysis, and associations between blood element patterns and diet were explored using sparse partial least squares (sPLS) regression. RESULTS: Blood concentrations were determined for the essential elements (in the order of most abundant) Zn > Cu > Se > Mn > Mo > Co, and the toxic metals Pb > As > Hg > Cd > Tl. The concentrations were in ranges that were similar to or sometimes more favorable than in other pregnant and non-pregnant European women. We identified two blood element patterns; one including Zn, Se and Mn and another including Hg and As. For the Zn-Se-Mn pattern, use of multimineral supplements was the most important dietary determinant, while a high score in the Hg-As pattern was mainly determined by seafood consumption. Concentrations of Mn, Cd and Co were significantly higher in women with iron deficiency (plasma ferritin < 12 µg/L) than in women with plasma ferritin ≥ 12 µg/L. CONCLUSION: Our study illustrates complex relationships and coexistence of essential and toxic elements. Their potential interplay adds to the challenges of studies investigating health effects related to either diet or toxicants.

Intestinal adenomas of Min-mice lack enterochromaffin cells, and have increased lysozyme production in non-Paneth cells.

BACKGROUND: Adenomatous polyposis coli (APC) are important in maintaining normal epithelial mucosa. Intestinal tissues with mutations in Apc have disturbed cell proliferation, differentiation and migration. Paneth and enterochromaffin cells were studied in the intestine and intestinal adenomas from Min-mice with heterozygote and homozygote mutations in Apc, respectively. MATERIALS AND METHODS: The presence of Paneth and enterochromaffin cells in normal intestine and adenomas from Min-mice was studied in sections stained with lysozyme/PAS and connexin32. RESULTS: Min-mice intestinal adenomas had an increased number of lysozyme-producing Paneth/goblet and non-Paneth cells and a reduced number of enterochromaffin cells. The large intestine had a significantly higher number of enterochromaffin cells than the small intestine and more were seen in the large intestine of Min- compared with wt-mice. CONCLUSION: Altered cell differentiation in adenomas might be caused by different response to Wnt-signalling, while an increased number of enterochromaffin cells in the large intestine is rather an effect of a heterozygous Apc(Min) mutation.

The influence of maternal dietary exposure to dioxins and PCBs during pregnancy on ADHD symptoms and cognitive functions in Norwegian preschool children.

BACKGROUND: Polychlorinated dibenzo-p-dioxins/dibenzofurans (dioxins) and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) with potentially adverse impact on child neurodevelopment. Whether the potential detrimental effects of dioxins and PCBs on neurodevelopment are of specific or unspecific character is not clear. OBJECTIVES: The purpose of the current study was to examine the influence of maternal dietary exposure to dioxins and PCBs on ADHD symptoms and cognitive functioning in preschoolers. We aimed to investigate a range of functions, in particular IQ, expressive language, and executive functions. MATERIAL AND METHODS: This study includes n=1024 children enrolled in a longitudinal prospective study of ADHD (the ADHD Study), with participants recruited from The Norwegian Mother and Child Cohort Study (MoBa). Boys and girls aged 3.5years participated in extensive clinical assessments using well-validated tools; The Preschool Age Psychiatric Assessment interview (PAPA), Stanford-Binet 5th revision (SB-5), Child Development Inventory (CDI), and Behavior Rating Inventory of Executive Function, Preschool version (BRIEF-P). Maternal dietary exposure to dioxins and PCBs was estimated based on a validated food frequency questionnaire (FFQ) answered mid-pregnancy and a database of dioxin and PCB concentrations in Norwegian foods. Exposure to dioxins and dioxin-like PCBs (dl-compounds) was expressed in total toxic equivalents (TEQ), and PCB-153 was used as marker for non-dioxin-like PCBs (ndl-PCBs). Generalized linear and additive models adjusted for confounders were used to examine exposure-outcome associations. RESULTS: Exposure to PCB-153 or dl-compound was not significantly associated with any of the outcome measures when analyses were performed for boys and girls together. After stratifying by sex, adjusted analyses indicated a small inverse association with language in girls. An increase in the exposure variables of 1 SD was associated with a reduction in language score of -0.2 [CI -0.4, -0.1] for PCB-153 and -0.2 [CI -0.5, -0.1] for dl-compounds in girls. For boys, exposure to PCB-153 or dl-compounds was not associated with language skills. The difference between sex-specific associations was not statistically significant (p-value=0.13). No sex-specific effects were observed for ADHD-symptoms, IQ scores, or executive functions. CONCLUSIONS: We found no indications that variation in current low-level exposure to PCB-153 or dl-compounds in Norway is associated with variation ADHD-symptoms, verbal/non-verbal IQ, or executive functions including working memory in preschoolers. However, our findings indicated that maternal dietary exposure to PCB-153 or dl-compounds during pregnancy was significantly associated with poorer expressive language skills in preschool girls, although the sex-specific associations were not significantly different.

Increased levels of PPARbeta/delta and cyclin D1 in flat dysplastic ACF and adenomas in Apc(Min/+) mice.

BACKGROUND: In Apc(Min/+) (Min; multiple intestinal neoplasia) mice two separate populations of aberrant crypt foci (ACF) develop in the colon after azoxymethane (AOM) exposure. ACF(Min), with a flat appearance, severe dysplasia and increased beta-catenin expression, are related to adenoma development, whereas classic ACF, with elevated structure, hyperplasia and normal beta-catenin level, are probably not. MATERIALS AND METHODS: The expressions of peroxisome proliferator-activated receptors (PPARs) beta/delta, cyclin D1 and beta-catenin in ACF, adenoma and normal tissue from AOM-treated Apc(Min/+) mice and a familial adenomatous polyposis (FAP) patient colon tumour were assessed by immunohistochemistry and immunoblotting. RESULTS: The flat ACF (ACF(Min)) displayed increased cytoplasmic levels of beta-catenin, and increased levels of cyclin D1 and PPARbeta/delta. In contrast, the expression in classic ACF resembled normal mucosa. Adenomas from Apc(Min/+) mice, as well as a FAP patient colon tumour, displayed increased nuclear and cytoplasmic levels of beta-catenin, and the same expression patterns of cyclin D1 and PPARbeta/delta as those found in flat ACF. CONCLUSION: In addition to activation of the Wnt signalling pathway in both flat ACF and in adenomas in Apc(Min/+) mice, the increased expression of PPARbeta/delta in these lesions could be a target for pro-inflammatory signals important for growth and reduced apoptosis.

Truncated mouse adenomatous polyposis coli reduces connexin32 content and increases matrilysin secretion from Paneth cells.

Heterozygous mutations in adenomatous polyposis coli (APC) is an early event in inheritable and sporadic colon cancer development. We recently found reduced connexin (Cx43) expression in intestinal cell lines with heterozygous Apc mutation. In this study we investigated Cx expression and the role of one mutated Apc allele in epithelia of multiple intestinal neoplasia (Min) mouse intestines by immunohistochemistry. Cx43 was not expressed in intestinal epithelia of Min and wild-type mice. Cx32 was specifically expressed in enterochromaffin cells in both mice types, and in Paneth cells of wild-type mice. In contrast, Min mice had nearly undetectable level of Cx32 in Paneth cells. Isolated small intestinal crypts from Min mice had markedly increased secretion of both lysozyme and matrilysin compared with wild-type mice. Absence of matrilysin in Min mice reduces adenoma development. Reduced Cx32 and increased matrilysin secretion from Paneth cells could be important to neoplastic development in the intestine.

The colon mitosis inhibitor pyroglutamyl-histidyl-glycine inhibits growth of non-tumorigenic colonic epithelial cells.

BACKGROUND: The colon mitosis inhibiting peptide pyroglutamyl-histidyl-glycine (pEHG) increases the expression of c-fos, fosB and egr-1 genes in the colon carcinoma cell line HT-29. However, the effect on non-tumorigenic colonic cells has not been investigated. MATERIALS AND METHODS: After exposure of the cell lines YAMC (from colon mucosa of Immorto mice) and IMCE (fromn Immorto-Min mouse hybrid) to pEHG, DNA-synthesis was analysed by H3-thymidine incorporation, apoptosis and necrosis by fluorescence microscopy, and cell cycle distribution by flow cytometry. RESULTS: pEHG inhibited DNA-synthesis with a maximal effect at 10(-8)-10(-9) M, but stimulated at 10(-4) M. It blocked cell flow through the cell cycle at GC/M after 8 h of treatment, but had no effect on apoptosis or necrosis at any concentration. A low concentration of ascorbic acid stabilised the cells, maybe as a free radical scavanger. CONCLUSION: pEHG inhibits flux at the G2/M transition, but has no effect on cell death.

Dietary exposure to dioxins and PCBs in a large cohort of pregnant women: results from the Norwegian Mother and Child Cohort Study (MoBa).

Exposure to dioxins and polychlorinated biphenyls (PCBs) during pregnancy and breastfeeding may result in adverse health effects in children. Prenatal exposure is determined by the concentrations of dioxins and PCBs in maternal blood, which reflect the body burden obtained by long term dietary exposure. The aims of this study were (1) to describe dietary exposure and important dietary sources to dioxins and PCBs in a large group of pregnant women and (2) to identify maternal characteristics associated with high dietary exposure to dioxins and PCBs. Dietary exposure to dioxins (sum of toxic equivalents (TEQs) from dioxin-like (dl) compounds) and PCB-153 in 83,524 pregnant women (gestational weeks 17-22) who participated in the Norwegian Mother and Child Cohort Study (MoBa) during the years 2002-2009 was calculated based on a food frequency questionnaire (FFQ) and a database of dioxin and PCB concentrations in Norwegian food. The median (interquartile range, IQR) intake of PCB-153 (marker of ndl-PCBs) was 0.81 (0.77) ng/kg bw/day. For dioxins and dioxin-like PCBs, the median (IQR) intake was 0.56 (0.37) pg TEQ/kg bw/day. Moreover, 2.3% of the participants had intakes exceeding the tolerable weekly intake (TWI) of 14pg TEQ/kg bw/week. Multiple regression analysis showed that dietary exposure was positively associated with maternal age, maternal education, weight gain during pregnancy, being a student, and alcohol consumption during pregnancy and negatively associated with pre-pregnancy BMI and smoking. A high dietary exposure to PCB-153 or dl-compounds (TEQ) was mainly explained by the consumption of seagull eggs and/or pate with fish liver and roe. Women who according to Norwegian recommendations avoid these food items generally do not have dietary exposure above the tolerable intake of dioxins and dl-PCBs.

Maternal dietary intake of dioxins and polychlorinated biphenyls and birth size in the Norwegian Mother and Child Cohort Study (MoBa).

Maternal diet not only provides essential nutrients to the developing fetus but is also a source of prenatal exposure to environmental contaminants. We investigated the association between dietary intake of dioxins and PCBs during pregnancy and birth size. The study included 50,651 women from the Norwegian Mother and Child Cohort Study (MoBa). Dietary information was collected by FFQs and intake estimates were calculated by combining food consumption and food concentration of dioxins, dioxin-like PCBs and non-dioxin-like PCBs. We used multivariable regression models to estimate the association between dietary intake of dioxins and PCBs and fetal growth. The contribution of fish and seafood intake during pregnancy was 41% for dietary dioxins and dioxin-like PCBs and 49% for dietary non-dioxin-like PCBs. Further stratified analysis by quartiles of seafood intake during pregnancy was conducted. We found an inverse dose-response association between dietary intake of dioxins and PCBs and fetal growth after adjustment for confounders. Newborns of mothers in the upper quartile of dioxin and dioxin-like PCBs intake had 62g lower birth weight (95% CI: -73, -50), 0.26cm shorter birth length (95% CI: -0.31, -0.20) and 0.10cm shorter head circumference (95% CI: -0.14, -0.06) than newborns of mothers in the lowest quartile of intake. Similar negative associations for intake of dioxins and dioxin-like PCBs were found after excluding women with intakes above the tolerable weekly intake (TWI=14pg TEQ/kg bw/week). The negative association of dietary dioxins and PCBs with fetal growth was weaker as seafood intake was increasing. No association was found between dietary dioxin and PCB intake and the risk for small-for-gestational age neonate. In conclusion, dietary intakes of dioxins and PCBs during pregnancy were negatively associated with fetal growth, even at intakes below the TWI.

The impact of commercial rodent diets on the induction of tumours and flat aberrant crypt foci in the intestine of multiple intestinal neoplasia mice.

A large variation in spontaneous tumour development in the multiple intestinal neoplasia (Min) mouse model between laboratories has been reported. The composition of the diet might be an important factor. We examined the impact of five commercial rodent diets: the natural ingredient breeding diet Harlan Teklad 2018 (HT), the purified breeding diet AIN93G, the natural ingredient maintenance diet RM1, and the purified maintenance diets AIN93M and AIN76A, on the spontaneous intestinal tumorigenesis in the Min mouse model. The Min mice were fed one of two breeding diets during gestation and until four weeks of age, thereafter one of the three maintenance diets. Min mice bred on the breeding diet HT had significantly higher numbers and incidences of tumours in the colon, but fewer tumours in the small intestine than the breeding diet AIN93G. The maintenance diet RM1 gave a significantly higher number of small intestinal and colonic tumours and precancerous lesions called flat aberrant crypt foci (ACF) compared with the maintenance diets AIN93M and AIN76A. These findings show the importance of defining the type of diet used in experimental intestinal carcinogenesis studies, and that the diet should be taken into consideration when comparing results from different studies with Min mice.

Development and validation of prediction models for blood concentrations of dioxins and PCBs using dietary intakes.

BACKGROUND: Dioxins and PCBs accumulate in the food chain and might exert toxic effects in animals and humans. In large epidemiologic studies, exposure estimates of these compounds based on analyses of biological material might not be available or affordable. OBJECTIVES: To develop and then validate models for predicting concentrations of dioxins and PCBs in blood using a comprehensive food frequency questionnaire and blood concentrations. METHODS: Prediction models were built on data from one study (n=195), and validated in an independent study group (n=66). We used linear regression to develop predictive models for dioxins and PCBs, both sums of congeners and 33 single congeners (7 and 10 polychlorinated dibenzo-p-dioxins and furans (PCDDs/PCDFs), 12 dioxin-like polychlorinated biphenyls (PCBs: 4 non-ortho and 8 mono-ortho), sum of all the 29 dioxin-like compounds (total TEQ) and sum of 4 non dioxin-like PCBs (∑ CB-101, 138, 153, 183=PCB(4)). We used the blood concentration and dietary intake of each of the above as dependent and independent variables, while sex, parity, age, place of living, smoking status, energy intake and education were covariates. We validated the models in a new study population comparing the predicted blood concentrations with the measured blood concentrations using correlation coefficients and Weighted Kappa (К(W)) as measures of agreement, considering К(W)>0.40 as successful prediction. RESULTS: The models explained 78% (sum dioxin-like compounds), 76% (PCDDs), 76% (PCDFs), 74% (no-PCBs), 69% (mo-PCBs), 68% (PCB(4)) and 63% (CB-153) of the variance. In addition to dietary intake, age and sex were the most important covariates. The predicted blood concentrations were highly correlated with the measured values, with r=0.75 for dl-compounds 0.70 for PCB(4), (p<0.001) and 0.66 (p<0.001) for CB-153. К(W) was 0.68 for sum dl-compounds 0.65 for both PCB(4) and CB-153. Out of 33 congeners 16 (13dl-compounds and 3 ndl PCBs) had К(W)>0.40. CONCLUSIONS: The models developed had high power to predict blood levels of dioxins and PCBs and to correctly rank subjects according to high or low exposure based on dietary intake and demographic information. These models underline the value of dietary intake data for use in investigations of associations between dioxin and PCB exposure and health outcomes in large epidemiological studies with limited biomaterial for chemical analysis.

Fish liver and seagull eggs, vitamin D-rich foods with a shadow: results from the Norwegian Fish and Game Study.

SCOPE: Fish liver, fish liver oil, oily fish and seagull eggs have been major sources of vitamin D for the coastal population of Norway. They also provide dioxin and polychlorinated dioxin-like compounds (dl-compounds), which may interfere with vitamin D homeostasis. We investigated whether serum 25-hydroxyvitamin D (25(OH)D) might be compromised by concomitant intake of dl-compounds. METHODS AND RESULTS: We studied 182 adults participating in the Norwegian Fish and Game Study. Participants who consumed fish liver and/or seagull eggs had higher dl-compound intake and blood concentrations than non-consumers (p < 0.001). Vitamin D intake was higher (p < 0.001), whereas serum 25(OH)D was lower (p = 0.029) in consumers than in non-consumers. Among non-consumers, vitamin D intake was associated with serum 25(OH)D (ß=1.06; 95% CI: 0.48, 1.63). This association was weaker among consumers (ß = 0.52; 95% CI: -0.05, 1.08), but strengthened when adjusted for retinol intake (ß = 0.66; 95% CI: 0.12, 1.21). The association between vitamin D intake and serum 25(OH)D did not seem to be compromised by intake of dl-compounds. CONCLUSION: To secure adequate vitamin D status while keeping the intake of dioxins and dl-polychlorinated biphenyls low, a healthy diet should include both supplemental vitamin D and oily fish. Despite high nutrient content, dietary fish liver and seagull eggs should be restricted, due to dl-compounds and possible vitamin A-D antagonism.