Assessment of chemical coexposure patterns based upon phthalate biomonitoring data within the 2007/2008 National Health and Nutrition Examination Survey.

As regulatory initiatives increasingly call for an understanding of the cumulative risks from chemical mixtures, evaluating exposure data from large biomonitoring programs, which may inform these cumulative risk assessments, will improve the understanding of occurrence and patterns of coexposures. Here we have analyzed the urinary metabolite data for six phthalates (di-butyl phthalate; di-isobutyl phthalate; butyl-benzyl phthalate; bis(2-ethylhexyl) phthalate; di-isononyl phthalate; and di-isodecyl phthalate) in the 2007/2008 National Health and Nutrition Examination Survey (NHANES) data set. For the total data set (N=2604), the co-occurrence of multiple phthalates at the upper percentile of exposure was infrequent. There were no individuals in the NHANES sample who were exposed to >95th percentiles for all six phthalates. For 75% of individuals, none of the six phthalates were above the 95th percentile of their respective exposure distributions. These data suggest that high exposure to multiple phthalates is infrequent in the NHANES population. This analysis solely focused on the pattern of contribution of individual phthalates to total exposure. It did not address the pattern of contribution to potential risk. The approach presented could potentially be used to provide insight into understanding the coexposure patterns for other chemicals.

Results of a 90-day inhalation study of dicyclopentadiene in B6C3F1 mice.

The objective of this inhalation study was to determine and evaluate the potential toxic effects of dicyclopentadiene vapor in mice exposed for 13-weeks of repeated inhalation. Four groups, each consisting of 45 male and 45 female B6C3F1 mice, were exposed to dicyclopentadiene vapor by inhalation 6 h/day, 5 days/week, for 13 weeks (64 exposures) at targeted concentrations of 0, 1.0, 5.0, or 50 ppm. An assessment of toxicity is carried out after 2, 6, and 13 weeks of inhalation exposures. Additionally, animals were evaluated during the recovery period of 4 or 13 weeks after the last exposure. Observations and measurements to assess toxicity include clinical observations, body weight, organ weights, serum chemistry, and hematologic, ophthalmologic, gross pathologic, and histologic evaluations. The only systemic effects observed were a few statistically significant changes in organ weights; but these were considered spurious in nature. Ten male and nine female mice in the highest exposure group died during the study, while no more than two mice died in any other group. However, the excess mortality was without an apparent etiology or association to exposure and was attributed to pulmonary congestion as a consequence of pulmonary irritation. Under the conditions of this study, these data demonstrated that in the absence of overt systemic toxicity, respiratory congestion has the predominant effect at the exposure levels of 50 ppm. This observation contributes to the Globally Harmonized System harmonized hazard classification of Single Target Organ Toxicity - Single Exposure (H335, may cause respiratory irritation) for this substance.

Estimates of daily di-isodecyl phthalate (DIDP) intake calculated from urinary biomonitoring data.

Biomonitoring of chemical species in biologic media can be a valuable tool in risk assessment since it informs directly on aggregate exposures. While advances in the analytical techniques required for biomonitoring have resulted in increased sensitivity for the detection of chemical species, the detection of a chemical substance in a biological medium (such as blood, urine or breast milk) does not mean that the chemical causes or is associated with an adverse health outcome. In this paper, intake estimates for di-isodecyl phthalate (DIDP), a high molecular weight general purpose plasticizer, were calculated from urinary biomonitoring data representing various population segments and geographic locales. From these data, intake estimates converge on a mean that is <1 µg/kg/day (95th% < 5 µg/kg/day). This intake estimate is at least two orders of magnitude lower than the health-based exposure guidance values (38-150 µg/kg/day) which have been proposed by regulatory authorities and other authoritative bodies as safe exposure levels.

A comprehensive review of intake estimates of di-isononyl phthalate (DINP) based on indirect exposure models and urinary biomonitoring data.

Di-isononyl phthalate (DINP) is a high molecular weight general purpose plasticizer used principally in the manufacture of flexible polyvinyl chloride (PVC) articles. DINP metabolites can be measured in biological media such as blood and urine. However, measurement of a substance in the blood or urine does not by itself mean that the chemical causes or is associated with adverse health outcomes. This is particularly pertinent given the advances in modern analytical techniques whereby ever diminishing trace amounts of substances can be detected. Therefore, it is a scientific necessity that risk assessors understand the relationship of biomonitoring data to estimation of exposure so that appropriate comparisons can be made to the no observed adverse effects levels (NOAELs) or other points of departure from toxicological studies in animals. In this paper, estimates of daily DINP intake are calculated for various population segments based on urinary biomonitoring data and are compared to estimates of exposure based on indirect methods and to health-based exposure guidance values. In general, intake estimates converge on a mean of 1-2µg/kg/day regardless of source of exposure or population cluster; a value 2-orders of magnitude lower than health-based exposure guidance values, ranging from 120 to 290µg/kg/day, which have been established by regulatory authorities and other authoritative bodies as representing acceptable levels.

Lung development in the Holtzman rat is adversely affected by gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that elicits a wide range of toxic effects on the developing organism. In this study, we demonstrate that the fetal and neonatal rat lung contains a responsive Ahr-signaling pathway which upon activation by a gestational exposure to TCDD, leads to altered lung development. Pregnant Holtzman rats received a single oral dose of TCDD (1.5 or 6 microg/kg) on gestation day (GD) 10 or a vehicle control with fetal and neonatal analysis occurring on GD20 or postnatal day (PND) 7. Components of the aryl hydrocarbon receptor (Ahr) signaling pathway (Ahr and Arnt) were identified in the fetal and neonatal lung tissue through the use of real-time PCR and immunohistochemical staining at both time points. Additionally, the Ahr-signaling pathway was found to be responsive to the gestational TCDD exposure as demonstrated by the induction of Cyp1a1, Cyp1b1, and Ahrr in both fetal and neonatal lung tissue. Morphometric analysis of GD20 and PND7 fixed lung tissue sections revealed that treated pups had significant decreases in total airspace area while having significantly wider tissue septa separating the airspaces as well as a decreased dry lung weight to body weight ratio when compared with controls; indicative of lung immaturity and hypoplasia. Finally, the assessment of respiratory mechanics on PND7 pups revealed functionally different pressure-volume curves in TCDD-exposed pups when compared with control animals. Together, these data identify a responsive Ahr-signaling pathway in the developing lung which may be related to the pulmonary immaturity and hypoplasia induced by TCDD and demonstrates that gestational exposure to TCDD alters lung development in such a manner that changes in lung morphology are associated with functional differences in respiratory mechanics.

Effects of Helicobacter infection on developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Holtzman rats.

To obtain accurate results from experiments in animal models, all potential confounding variables must be identified and controlled. The authors examined the effects of Helicobacter infection on developmental toxicity resulting from exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent and ubiquitous environmental contaminant. They administered different doses of TCDD to timed pregnant Helicobacter-positive and Helicobacter-negative Holtzman rats and evaluated fetal and neonatal viability. They also assessed hepatic cytochrome P450 induction and activity of the gene Cyp1a1, which are classic indicators of TCDD exposure. All rats were affected by TCDD, and Helicobacter infection seemed to have little influence on rats' susceptibility to the compound.

Gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters retinoid homeostasis in maternal and perinatal tissues of the Holtzman rat.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), one of the most widely studied environmental contaminants, causes a variety of adverse health effects including teratogenesis and altered development which may be related to disruptions in retinoid homeostasis. The purpose of this study was to determine the effect that gestational administration of TCDD has on retinoid homeostasis in both pregnant Holtzman rats and developing fetuses and neonates. A single oral dose of TCDD (0, 1.5, 3, or 6 microg/kg) was administered to pregnant rats on gestation day 10, with fetuses analyzed on gestation days 17 and 20, and neonates analyzed on post natal day 7. Exposure to TCDD generally produced decreases in the concentrations of retinyl esters, such as retinyl palmitate, and retinol in maternal and perinatal liver and lung, while increasing levels in the maternal kidney. Additionally, perinatal hepatic retinol binding protein 1-dependent retinyl ester hydrolysis was also decrease by TCDD. Sensitivity of the developing perinates to TCDD appeared to have an age-related component demonstrated by an increased rate of mortality and significant alterations to body weight and length on post natal day 7 relative to that observed at gestation day 20. A unique observation made in this study was a significant decrease in lung weight observed in the perinates exposed to TCDD. Taken together, these data demonstrate that TCDD significantly alters retinoid homeostasis in tissues of the developing fetus and neonate, suggesting that their unique sensitivity to TCDD may at least be in part the result of altered retinoid homeostasis.

Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the hamster, rat and guinea pig.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant capable of causing a wide variety of adverse health effects including teratogenesis and altered development. The objective of this study was to compare the developmental toxicity of TCDD in the hamster, rat and guinea pig, which in mature animals exhibit a relatively low, medium and high sensitivity to TCDD, respectively. A single oral dose of TCDD was administered to pregnant rats (0, 1.5, 3.0, 6.0 or 18.0microg/kg) on gestation day 10, pregnant hamsters (0, 1.5, 3.0, 6.0 or 18.0microg/kg) on gestation day 9 and pregnant guinea pigs (0, 0.15 or 1.5microg/kg) on gestation day 14 with fetal analysis on gestation day 20, 15 and 56, respectively. The developmental toxicity of TCDD in the three species included increased fetal mortality, alterations to fetal body weight, body length, organ weight and significant changes to the fetal white blood cell differential counts. Additionally, teratogenic responses were observed in the hamster and rat consisting of cleft palate, kidney congestion, hydronephrosis and intestinal hemorrhaging. Furthermore, the results from this study demonstrate that despite the up to 5000-fold interspecies variability to the acute lethal potency of TCDD observed in mature guinea pigs, rats and hamsters, the developing fetus is uniquely vulnerable to gestational TCDD exposure and displays approximately a 10-fold variability in fetal lethal potency in these species. Together, these results will assist efforts to reduce the uncertainty in the risk assessment for TCDD in sensitive populations, such as the developing embryo and fetus.