An adaptable internal dose model for risk assessment of dietary and soil dioxin exposures in young children.

An adaptable model is presented for assessing the blood lipid concentrations of polychlorodibenzodioxins and polychlorodibenzofurans (PCDD/Fs) from dietary (breast milk, formula, milk, and other foods) and soil pathway exposures (soil ingestion and dermal contact) utilizing age-specific exposure and intake estimates for young children. The approach includes a simple one-compartment (adipose volume) toxicokinetic model that incorporates empirical data on age-dependent half-lives and bioavailability of PCDD/F congeners, child body size and intake rates, and recent data on breast milk and food dioxin levels. Users can enter site-specific soil concentration data on 2,3,7,8-chlorinated PCDD/F congeners for specific assessment of body burden changes from soil pathways in combination with background dietary exposures from birth through age 7 years. The model produces a profile of the estimated PCDD/F concentration in blood lipid (in World Health Organization 1998 dioxin toxic equivalents) versus time for a child from birth through age 7 years. The peak and time-weighted average (TWA) internal dose (defined as blood lipid dioxin toxic equivalents) for a variety of specific child exposure assumptions can then be compared to safe internal dose benchmarks for risk assessment purposes, similar to an approach taken by United States Environmental Protection Agency for assessing child lead exposures. We conclude that this adaptable toxicokinetic model can provide a more comprehensive assessment of potential health risks of PCDD/Fs to children because it integrates recent empirical findings on PCDD/F kinetics in humans and allows users to assess contributions from varied dietary and site-specific environmental exposure assumptions.

Refinements on the age-dependent half-life model for estimating child body burdens of polychlorodibenzodioxins and dibenzofurans.

We modified our prior age-dependent half-life model to characterize the range of child (ages 0-7) body burdens associated with dietary and environmental exposure to polychlorodibenzodioxins and furans (PCDD/Fs). Several exposure scenarios were evaluated. Infants were assumed to be either breast-fed or formula-fed from birth to 6 months of age. They then received intakes of PCDD/Fs through age 7 from foods based on weighted means estimates [JECFA, 2001. Joint FAO/WHO Committee on Food Additives. Fifty-seventh meeting, Rome, June 5-14 , 2001, pp. 24-40], and with or without exposures (ingestion and dermal) to urban residential soils at 1ppb TCDD toxic equivalents (TEQ). A one-compartment (adipose volume) toxicokinetic model for TCDD described by Kreuzer [Kreuzer, P.F., Csanady, Gy.A., et al., 1997. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. Arch. Toxicol. 71, 383-400] was expanded to include the key non-TCDD congeners in human breast milk and adipose tissues, and two model parameter refinements were examined: (1) use of updated and more detailed age-correlated body fat mass data [CDC, 2000. Centers for Disease Control. CDC Growth Charts: United States. Advance Data from Vital and Health Statistics of the Centers for Disease Control and Prevention, National Center for Health Statistics, Number 314, December 2000]; (2) use of breast milk PCDD/F concentration data from sampling completed in 2000-2003 [Wittsiepe, J., Fürst, P., et al., 2004. PCDD/F and dioxin-like PCB in human blood and milk from German mothers. Organohalogen Compd. 66, 2865-2872]. The updated body fat mass data nearly halved the predicted peak body burden for breast-feeding and lowered the time-weighted average (TWA) body burdens from ages 0-7 by 30-40% for breast-fed and formula-fed infants. Combined use of the updated breast milk PCDD/F concentration and body fat mass data increased the contribution of breast-feeding but reduced TWA body burdens from diet and soil. We conclude that further refinements are needed, but reliance on these better data sets for body fat mass and breast milk PCDD/F concentration significantly improves the model's ability to accurately predict body burdens during early childhood.

Age- and concentration-dependent elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso children.

OBJECTIVE: Pharmacokinetic and statistical analyses are reported to elucidate key variables affecting 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elimination in children and adolescents. DESIGN: We used blood concentrations to calculate TCDD elimination half-life. Variables examined by statistical analysis include age, latency from exposure, sex, TCDD concentration and quantity in the body, severity of chloracne response, body mass index, and body fat mass. PARTICIPANTS: Blood was collected from 1976 to 1993 from residents of Seveso, Italy, who were < 18 years of age at the time of a nearby trichlorophenol reactor explosion in July 1976. RESULTS: TCDD half-life in persons < 18 years of age averaged 1.6 years while those > or =18 years of age averaged 3.2 years. Half-life is strongly associated with age, showing a cohort average increase of 0.12 year half-life per year of age or time since exposure. A significant concentration-dependency is also identified, showing shorter half-lives for TCDD concentrations > 400 ppt for children < 12 years of age and 700 ppt when including adults. Moderate correlations are also observed between half-life and body mass index, body fat mass, TCDD mass, and chloracne response. CONCLUSIONS: Children and adolescents have shorter TCDD half-lives and a slower rate of increase in half-life than adults, and this effect is augmented at higher body burdens. RELEVANCE: Modeling of TCDD blood concentrations or body burden in humans should take into account the markedly shorter elimination half-life observed in children and adolescents and concentration-dependent effects observed in persons > 400-700 ppt.

Elimination half-lives of selected polychlorinated dibenzodioxins and dibenzofurans in breast-fed human infants.

Elimination half-life estimates for several polychlorinated dibenzodioxins/furans (PCDD/F) were calculated by modeling the blood and breast milk concentrations in two breast-fed human infants as reported by Abraham et al. (1996, 1998). Our analysis differs from that of other investigators in that we analyzed individual dioxin and furan congeners while the other studies considered TCDD only and we determined the half-lives in infants, rather than simply predicting body burdens in infants and older children. The average half-life values for each consistently measurable congener were determined to be less than about 6 mo and did not vary substantially between the two infants studied. The average elimination half-life values for 2,3,7,8-tetraCDD, 1,2,3,7,8-pentaCDD, 1,2,3,6,7,8-hexaCDD, 1,2,3,4,6,7,8-heptaCDD, and octaCDD were 0.40, 0.32, 0.39, 0.32, and 0.46 yr, respectively, and 0.27 yr for 2,3,4,7,8-pentaCDF. These values are in stark contrast with the 7 to 15+ yr values reported for these congeners in human adults (Michalek et al., 1996). These much shorter half-life values, likely attributable to rapid growth of the adipose tissue volume and enhanced fecal excretion of dioxins for breast-fed infants, explain why the much higher daily dioxin intake during breastfeeding does not translate to proportionately higher tissue concentrations. Thus, the shorter half-life of dioxins during breastfeeding needs to be considered when evaluating the dioxin hazard to children.

Review of the carcinogenic activity of diethanolamine and evidence of choline deficiency as a plausible mode of action.

Diethanolamine (DEA) is a chemical used widely in a number of industries and is present in many consumer products. Studies by the National Toxicology Program (NTP) have indicated that lifetime dermal exposure to DEA increased the incidence and multiplicity of liver tumors in mice, but not in rats. In addition, DEA was not carcinogenic when tested in the Tg.Ac transgenic mouse model. Short-term genotoxicity tests have yielded negative results. In view of these apparent inconsistencies, we have critically evaluated the NTP studies and other data relevant to assessing the carcinogenic potential of DEA. The available data indicate that DEA induces mouse liver tumors by a non-genotoxic mode of action that involves its ability to cause choline deficiency. The following experimental evidence supports this hypothesis. DEA decreased the hepatic choline metabolites and S-adenosylmethionine levels in mice, similar to those observed in choline-deficient mice. In contrast, DEA had no effect in the rat, a species in which it was not carcinogenic at a maximum tolerated dose level. In addition, a consistent dose-effect relationship had been established between choline deficiency and carcinogenic activity since all DEA dosages that induced tumors in the NTP studies were also shown to cause choline deficiency. DEA decreased phosphatidylcholine synthesis by blocking the cellular uptake of choline in vitro, but these events did not occur in the presence of excess choline. Finally, DEA induced transformation in the Syrian hamster embryo cells, increased S-phase DNA synthesis in mouse hepatocytes, and decreased gap junctional intracellular communication in primary cultured mouse and rat hepatocytes, but all these events were prevented with choline supplementation. Since choline is an essential nutrient in mammals, this mode of action is qualitatively applicable to humans. However, there are marked species differences in susceptibility to choline deficiency, with rats and mice being far more susceptible than other mammalian species including humans. These differences are attributed to quantitative differences in the enzyme kinetics controlling choline metabolism. The fact that DEA was carcinogenic in mice but not in rats also has important implications for human risk assessment. DEA has been shown to be less readily absorbed across rat and human skin than mouse skin. Since a no observed effect level for DEA-induced choline deficiency in mice has been established to be 10 mg/kg/d, this indicates that there is a critical level of DEA that must be attained in order to affect choline homeostasis. The lack of a carcinogenic response in rats suggests that exposure to DEA did not reach this critical level. Since rodents are far more sensitive to choline deficiency than humans, it can be concluded that the hepatocarcinogenic effect of DEA in mice is not predictive of similar susceptibility in humans.

Subchronic inhalation neurotoxicity studies of ethyl acetate in rats.

Rats were exposed to 0, 350, 750 or 1500 ppm of ethyl acetate by inhalation for 6 h per day, 5 days per week for 13 weeks. Functional observational battery (FOB) and motor activity tests occurred on non-exposure days during weeks 4, 8 and 13, after which tissues were microscopically examined for neuropathology. A subset of rats was monitored during a 4-week recovery period. Exposure to 750 and 1500 ppm, diminished behavioral responses to unexpected auditory stimuli during the exposure session and appeared to be an acute sedative effect. There were no signs of acute intoxication 30 min after exposure sessions ended. Rats exposed to 750 and 1500 ppm had reduced body weight, body weight gain, feed consumption, and feed efficiency, which fully or partially recovered within 4 weeks. Reductions in body weight gain and feed efficiency were observed in male rats exposed to 350 ppm. The principal behavioral effect of subchronic exposure was reduced motor activity in the 1500 ppm females, an effect that was not present after the 4-week recovery period. All other FOB and motor activity parameters were unaffected, and no pathology was observed in nervous system tissues. Operant sessions were conducted in another set of male rats preconditioned to a stable operant baseline under a multiple fixed ratio-fixed interval (FR-FI) schedule of food reinforcement. FR response rate, FR post-reinforcement pause duration, and the pattern of FI responding were not affected during or after the exposure series. In contrast, within-group FI rate for the treatment groups increased over time whereas those of the controls decreased. A historical control group, however, also showed a similar pattern of increase, indicating that these changes did not clearly represent a treatment-related effect. Results from these studies indicate a LOEL of 350 ppm for systemic toxicity based on the decreased body weight gain in male rats, and a LOEL of 1500 ppm for neurotoxicity based on the transient reduction in motor activity in female rats. In conclusion, there was no evidence that subchronic exposure up to 1500 ppm ethyl acetate produced any enduring neurotoxic effects in rats.