In June 2005, a World Health Organization (WHO)-International Programme on Chemical Safety expert meeting was held in Geneva during which the toxic equivalency factors (TEFs) for dioxin-like compounds, including some polychlorinated biphenyls (PCBs), were reevaluated. For this reevaluation process, the refined TEF database recently published by Haws et al. (2006, Toxicol. Sci. 89, 4-30) was used as a starting point. Decisions about a TEF value were made based on a combination of unweighted relative effect potency (REP) distributions from this database, expert judgment, and point estimates. Previous TEFs were assigned in increments of 0.01, 0.05, 0.1, etc., but for this reevaluation, it was decided to use half order of magnitude increments on a logarithmic scale of 0.03, 0.1, 0.3, etc. Changes were decided by the expert panel for 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.3), 1,2,3,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.03), octachlorodibenzo-p-dioxin and octachlorodibenzofuran (TEFs = 0.0003), 3,4,4',5-tetrachlorbiphenyl (PCB 81) (TEF = 0.0003), 3,3',4,4',5,5'-hexachlorobiphenyl (PCB 169) (TEF = 0.03), and a single TEF value (0.00003) for all relevant mono-ortho-substituted PCBs. Additivity, an important prerequisite of the TEF concept was again confirmed by results from recent in vivo mixture studies. Some experimental evidence shows that non-dioxin-like aryl hydrocarbon receptor agonists/antagonists are able to impact the overall toxic potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds, and this needs to be investigated further. Certain individual and groups of compounds were identified for possible future inclusion in the TEF concept, including 3,4,4'-TCB (PCB 37), polybrominated dibenzo-p-dioxins and dibenzofurans, mixed polyhalogenated dibenzo-p-dioxins and dibenzofurans, polyhalogenated naphthalenes, and polybrominated biphenyls. Concern was expressed about direct application of the TEF/total toxic equivalency (TEQ) approach to abiotic matrices, such as soil, sediment, etc., for direct application in human risk assessment. This is problematic as the present TEF scheme and TEQ methodology are primarily intended for estimating exposure and risks via oral ingestion (e.g., by dietary intake). A number of future approaches to determine alternative or additional TEFs were also identified. These included the use of a probabilistic methodology to determine TEFs that better describe the associated levels of uncertainty and "systemic" TEFs for blood and adipose tissue and TEQ for body burden.

C.Båvik and V.Sapin contributed equally to this workThe gene encoding cellular retinol (ROL, vitA)-binding protein type I (CRBPI) has been inactivated. Mutant mice fed a vitA-enriched diet are healthy and fertile. They do not present any of the congenital abnormalities related to retinoic acid (RA) deficiency, indicating that CRBPI is not indispensable for RA synthesis. However, CRBPI deficiency results in an~50% reduction of retinyl ester (RE) accumulation in hepatic stellate cells. This reduction is due to a decreased synthesis and a 6-fold faster turnover, which are not related to changes in the levels of RE metabolizing enzymes, but probably reflect an impaired delivery of ROL to lecithin:retinol acyltransferase. CRBPI-null mice fed a vitA-deficient diet for 5 months fully exhaust their RE stores. Thus, CRBPI is indispensable for efficient RE synthesis and storage, and its absence results in a waste of ROL that is asymptomatic in vitA-sufficient animals, but leads to a severe syndrome of vitA deficiency in animals fed a vitA-deficient diet.

The ability of the commercial polybrominated diphenyl ether (PBDE) preparation Bromkal 70-5 DE to alter thyroid hormone and vitamin A levels as well as microsomal enzyme activities was compared with that of the commercial polychlorinated biphenyl (PCB) preparation Aroclor 1254 in orally exposed female rats (Sprague-Dawley) and mice (C57BL/6 N). Additional mice were exposed to the PBDE congener 2,2',4,4'-tetrabromodiphenyl ether (DE-47), or to the PCB congener 2,3,3',4,4'-pentachlorobiphenyl (CB-105). For 14 days the animals were given approximately isomolar daily oral doses of Aroclor 1254, CB-105 (both 10 mg/kg body weight), Bromkal 70-5 DE or DE-47 (both at 18 mg/kg body weight). In addition, further groups of rats and mice received a higher dose of Bromkal 70-5 DE, 36 mg/kg body weight. Bromkal 70-5 DE and DE-47 decreased plasma free and total thyroxine (T4) levels in both rats and mice, although with lower potency than that of Aroclor 1254 and CB-105. By contrast, thyroid-stimulating hormone (TSH) levels were not significantly changed in any of the groups. Reduction of hepatic vitamin A levels was seen in rats after Aroclor 1254 and Bromkal 70-5 DE exposure. A similar tendency was seen also in mice, but the effects were significant only for concentration data and not the total amount. Induction ofmicrosomal phase I enzymes, measured as ethoxy, methoxy and pentoxy resorufin O-dealkylase (EROD, MROD, PROD) activities, was greatest after exposure to Aroclor 1254/CB-105 but were also significant in the Bromkal 70-5 DE/DE-47-treated groups. However, induction of uridine diphosphoglucuronosyl transferase (UDPGT) was small and for most groups insignificant. In conclusion, the PBDE compounds studied, although having a lower potency than the PCB compounds, decreased thyroxine and vitamin A levels and induced microsomal enzyme activities. Rats were more sensitive to the observed effects than mice. Microsomal phase I activity might be related, directly or indirectly, to the T4 and vitamin A effects, whereas several factors (such as weak enzyme induction and lack of correlation with altered T4 and vitamin A levels) argue against any UDPGT-related effects.

BackgroundPhthalates may pose a risk for perinatal developmental effects. An important question relates to the choice of suitable biological matrices for assessing exposure during this period.ObjectivesThis study was designed to measure the concentrations of phthalate diesters or their metabolites in breast milk, blood or serum, and urine and to evaluate their suitability for assessing perinatal exposure to phthalates.MethodsIn 2001, 2–3 weeks after delivery, 42 Swedish primipara provided breast milk, blood, and urine samples at home. Special care was taken to minimize contamination with phthalates (e.g., use of a special breast milk pump, heat treatment of glassware and needles, addition of phosphoric acid).ResultsPhthalate diesters and metabolites in milk and blood or serum, if detected, were present at concentrations close to the limit of detection. By contrast, most phthalate metabolites were detectable in urine at concentrations comparable to those from the general population in the United States and in Germany. No correlations existed between urine concentrations and those found in milk or blood/serum for single phthalate metabolites. Our data are at odds with a previous study documenting frequent detection and comparatively high concentrations of phthalate metabolites in Finnish and Danish mothers’ milk.ConclusionsConcentrations of phthalate metabolites in urine are more informative than those in milk or serum. Furthermore, collection of milk or blood may be associated with discomfort and potential technical problems such as contamination (unless oxidative metabolites are measured). Although urine is a suitable matrix for health-related phthalate monitoring, urinary concentrations in nursing mothers cannot be used to estimate exposure to phthalates through milk ingestion by breast-fed infants.

Suspensions of thymocytes from young rats were incubated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which resulted in a sustained increase in cytosolic free Ca2+ concentration followed by DNA fragmentation and loss of cell viability. Both the Ca2+ increase and DNA fragmentation were prevented in cells treated with the inhibitor of protein synthesis, cycloheximide, and DNA fragmentation and cell killing were not detected when cells were incubated in a "Ca2+-free" medium or pretreated with high concentrations of the calcium probe, quin-2 tetraacetoxymethyl ester. These results indicate that TCDD can kill immature thymocytes by initiating a suicide process similar to that previously described for glucocorticoid hormones.