* Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 275997270; and
U. S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Experimental Toxicology Division, Research Triangle Park, North Carolina 27711
Received April 30, 1999; accepted August 30, 1999
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ABSTRACT |
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Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD; toxicokinetics; disposition; body burden; embryo; fetus.
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INTRODUCTION |
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TCDD and dioxinlike compounds adversely affect reproduction and development in part due to its ability to alter hormone and receptor levels in the endocrine system (Birnbaum, 1994b). Exposure to 0.064 µg TCDD/kg in female Holtzman rats on gestation day (GD) 15 decreased epididymal sperm reserves in male pups but produced no overt signs of toxicity in the pups or dams (Mably et al., 1992
). Studies by Gray and coworkers examined the adverse effects in male and female Long Evans (LE) pups that were associated with exposure during critical periods of development. For example, a dose of 1.0 µg TCDD/kg on GD8 produced a broad spectrum of effects such as malformations in the external genitalia, premature reproductive senescence, enhanced incidence of constant estrous, and cystic endometrial hyperplasia in female LE rat pups (Gray and Ostby, 1995
). In male offspring, this dose was associated with a persistent reduction in sperm counts (Gray et al., 1995
). In addition, exposure to 1.0 µg TCDD/kg on GD15 produced a narrower spectrum of adverse effects, although the magnitude of the responses was much greater (Gray et al., 1995
). For example, administration of 1.0 µg TCDD/kg on GD15 produced a greater decrease in cauda epididymal sperm numbers and ejaculated sperm numbers in males as compared to administration on GD8. In females, the GD15 group had a higher incidence of clefting of the phallus and a permanent thread of tissue across the vagina as compared to the GD8 group (Gray and Ostby, 1995
). Results from Gray and coworkers show that administration of TCDD on GD15 is more detrimental to the offspring than an equivalent dose administered on GD8 with respect to male reproductive endpoints and in inducing malformations in the external genitalia of females (Gray et al., 1995
; Gray and Ostby, 1995
).
Recent studies in our laboratory have shown that exposure to 1.15 µg TCDD/kg during a critical period of organogenesis (GD8) results in rat fetal tissue concentrations of 2040 pg/g between GD9 and GD21 (Hurst et al., 1998). Although very little of this chemical reaches the developing fetus, it is still sufficient to produce adverse developmental effects. Therefore, our objective was to expand on these observations by conducting a dose-response study on GD15, which is the onset of sexual differentiation, in order to determine maternal and fetal tissue concentrations of TCDD. In this study, LE rats were dosed by gavage on GD15 with 0.05, 0.20, 0.80, or 1.0 µg TCDD/kg, and tissue concentrations were measured on GD16 and GD21. This information is useful to determine how fetal tissue concentration relates to a response in light of the fact that dosing on different gestational days produces different responses as well as a varying magnitude of the response.
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MATERIALS AND METHODS |
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Animals and treatments.
Eight-week-old, time-pregnant Long Evans rats (200250g) were obtained from Charles River Breeding Laboratories (Raleigh, NC) on GD9. The day following overnight mating, with evidence of a copulatory plug, is designated as GD0 by Charles River Laboratories. Animals were housed individually in clear plastic cages with hardwood bedding (Beta Chips, Northeastern Products, Warrensburg, NY). Animals were maintained during pregnancy on Laboratory Rodent Diet (#5001, PMI Feeds, Inc., St. Louis, MO) and unpurified tap water ad libitum in a room with a 12:12-h photoperiod and a temperature of 2024°C with a relative humidity of 4050%.
Experimental design and treatments.
Five time-pregnant rats were assigned to each group. Rats received a single oral dose of 0.05, 0.20, 0.80, or 1.0 µg [3H]-TCDD/kg in 5 ml corn oil/kg on GD15. The dams were anesthetized with CO2 on GD16 or GD21, and 5 ml of blood was removed via cardiac puncture. Animals were terminated by cervical dislocation while under anesthesia. The following maternal tissues were removed and weighed: liver, adipose, thymus, muscle, and skin (ears). On GD16 and GD21, four fetuses from each litter were randomly selected to determine the amount of TCDD reaching the entire fetus. The remaining fetuses were subdivided into urogenital tract, liver, head, remaining tissue (body), and placenta. All the fetal tissues within a dam were assayed individually except for the urogenital tract. This tissue was so small that all the urogenital tracts within an individual dam were pooled to determine TCDD concentrations. On GD21 only, whole fetuses were homogenized in a Waring blender with liquid nitrogen until a fine powder was formed. Three 250-mg samples of the resulting powder were prepared for sample oxidation to determine TCDD concentration.
Oxidation and quantitation of samples.
Tissues were oxidized using a Packard 307 Sample Oxidizer with an Oximate 80 Robotic Operator (Packard, Downers Grove, IL) and oxidized samples were analyzed in a Beckman Model LS6000 LL liquid scintillation spectrometer using Monophase S (Packard, Downers Grove, IL). Previous studies from our laboratory indicate that >95% [3H]-TCDD present in tissues is recovered as parent compound (Kedderis et al., 1991).
Data analysis.
Calculation of percentage total dose and tissue volumes for adipose, muscle, and skin were experimentally determined on GD16 and GD21 as described by Hurst et al. (1998). For both time points, blood mass was assumed to be 7.4% of body weight (International Life Sciences Institute, 1994). The data was analyzed in the following dose metric units: % dose/tissue, % dose/g tissue, ng TCDD/tissue, and ng TCDD/g tissue. Maternal body burdens were estimated based on analysis of dioxin in the following maternal tissues: liver, adipose, skin, and muscle. It was assumed that >90% of the body burden was due to the amount of TCDD present in these tissues.
Statistical methods.
Intergroup comparisons were performed by a one-way analysis of variance (ANOVA) (Statview, Abacus Concepts, Inc., Berkeley, CA). When statistically significant effects were detected in the overall analysis of variance, means were compared using Scheffe's F test. When data were collected on more than one fetus per litter, the data were analyzed using litter means rather than individual fetus values. Differences between treatment groups were considered significantly different when p < 0.05. All data in the tables are presented as means ± standard deviations.
Model fitting.
This study was designed to evaluate the hypothesis that fetal tissue concentration of TCDD is sufficient to predict the intensity of developmental abnormalities. The approach involved incidences of various abnormalities for a range of maternal doses administered on GD15 and a single dose administered on GD8. In separate experiments, estimates of maternal and fetal TCDD concentrations were determined for the same administered dosages. A dose-response model was designed for each of four developmental abnormalities (ejaculated sperm counts and delayed puberty in males and urethra-phallus distance and incidence of vaginal thread in females), which related the incidence of the endpoint after GD15 dosing to fetal tissue concentration. These four endpoints were selected because they were consistently measured at the same postnatal time point in each of the papers by Gray and coworkers (Gray et al., 1995; Gray and Ostby, 1995
; Gray et al., 1997a
; Gray et al., 1997b
). In addition, these responses were the most severely affected, which enabled a comparison of tissue concentration and adverse effects to be made. The question was then asked whether tissue concentration following GD8 exposure results in the incidence of developmental effects as predicted by the dose-response model.
The appropriate transformation for the dependent variable (developmental abnormality) was determined to make the variances homogeneous and unrelated to the group means and to make the population residuals within the groups approximately normally distributed. The dependent variable was first examined on its original scale, followed by log-square-root and three-quarters-powertransformed. Normality was checked by examining normal score plots of the residuals after subtracting off the group means, looking at graphs of within-group standard deviations versus group means, and boxplots of residuals for each group. As soon as a transformation was found that provided a satisfactory residual distribution and standard deviation to mean relationship, the search ended.
The fitted models took into account the two blocks in the study (group 1: GD15 doses 00.8 µg TCDD/kg; group 2: control and 1.0 µg TCDD/kg on GD8 and GD15). The full models always had the following form for the dependent variable yg in group g and independent variable t (where either y or t, or both, may be transformed): if g is 1, y1 = a1 + bt; if g is 2, and data are for GD15, y2 = a2 + bt; if g is 2 and the data are for GD8, y2 = a2 + + bt. This allows for the possibility that control values may differ between the two blocks, and fits a common slope to the values in both blocks. The parameter
is an estimate of the difference between the mean GD8 value and the value predicted by the model for the GD15 data. Its value should be zero if tissue concentration is all that is needed to predict an outcome. The log-likelihood value for the various fitted models relative to that derived from the model in which each distinct dose and gestation group has a separate mean is used as a goodness-of-fit test.
All continuous endpoints were fit using data at the level of the individual pup or fetus. To accommodate the nested nature of the design (pups within litters), linear mixed effects models (Lindstrom and Bates, 1988) were fit by maximum likelihood using the function lme in Splus (version 3.4, Mathsoft Corporation, Seattle, Washington).
The variable vaginal thread is a dichotomous variable, so the above procedure was modified somewhat. To accommodate the nested design, the Rao-Scott transformation was used (Rao and Scott, 1992; Krewski and Zhu, 1995
) and logistic models were fit using the Splus function glm. This has been shown to be an efficient procedure (Fung et al., 1998
) and is simpler to implement than other approaches to nested design. Methods appropriate to measurement error models are formally appropriate for these data, as the mean tissue concentrations are measured with error. However, the proportion of the overall spread of tissue concentrations that is attributable to measurement error is so small that we have ignored this effect.
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RESULTS |
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Fetal TCDD Tissue Concentrations
GD16.
A dose of 0.05 µg TCDD/kg resulted in a concentration of 5 pg/g in a single fetus (0.02% of administered dose) (Table 2). This increased to 56 pg/g after exposure to 1.0 µg TCDD/kg. Individual fetuses were subdivided into liver, urogenital tract, head, and body to determine whether TCDD was preferentially sequestered within a fetus. A dose of 0.05 µg TCDD/kg produced a concentration of 4 pg/g in fetal liver, 5 pg/g in a head, 6 pg/g in a body, and 4 pg/g in the urogenital tract (Table 3
). At a dose of 0.20, 0.80, and 1.0 µg TCDD/kg, there was approximately 14, 38, and 52 pg TCDD/g within each of the three fetal tissues (head, body, and urogenital tract), respectively. To determine the amount of TCDD reaching the entire fetal compartment, TCDD levels in all the fetuses and placentas were summed. At the low dose (0.05 µg/kg), the fetal compartment contained 0.5% of the administered dose, which resulted in a concentration of 7 pg TCDD/g (Table 2
). At the higher doses (0.2, 0.8, and 1.0 µg/kg) the fetal compartment contained 0.3, 0.2, and 0.2% of the administered dose, respectively.
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Dose-Response Relationships
Although the administered dose is often associated with a response, the body burden may be a more appropriate dose metric for a persistent, poorly metabolized chemical such as TCDD. Gray and coworkers conducted several studies in which the reproductive and developmental effects of gestational TCDD-exposure were assessed. Specifically, Gray and coworkers (Gray et al., 1995; Gray and Ostby, 1995
) examined the adverse effects in pups exposed to a single dose of 1.0 µg TCDD/kg on GD8 or GD15. In addition, they conducted a dose-response study in which the dams received 0, 0.05, 0.20, or 0.80 µg TCDD/kg on GD15 and the adverse effects in the pups were measured (Gray et al., 1997a
; Gray et al., 1997b
). Therefore, using response data from Gray and coworkers (Gray et al., 1995
; Gray and Ostby, 1995
; Gray et al., 1997a
; Gray et al., 1997b
), GD16 fetal tissue concentrations, which were measured in the present study, were plotted to relate tissue concentration to the incidence of developmental effect after similar exposures (Figs. 14
). Note: All the statistical work was based on scaling the tissue concentrations following GD8 exposure by 1/1.15 (Hurst et al., 1998
), as GD8 developmental results are based on 1.00 µg TCDD/kg (Gray et al., 1995
; Gray and Ostby, 1995
). On GD16, the model adequately predicts the response (sperm count and day of puberty in males; urethra-phallus distances and incidence of vaginal thread in females) associated with the concentration of TCDD in a single fetus after different acute exposures. For example, a dose of 1.15 µg TCDD/kg on GD8 produced a concentration of 16 pg/g on GD16 in a single fetus (Hurst et al., 1998
). This tissue concentration (16 pg/g) predicts urethra-phallus distance in female pups based on GD16 tissue concentrations following GD15 administration (Fig. 3
). In addition, fetal TCDD concentration predicts ejaculated sperm counts and day of puberty in males (Figs. 1 and 2
). However, GD8 exposure to 1.15 µg TCDD/kg slightly underpredicts the incidence of vaginal thread formation (Fig. 4
). This may be due to the large variability in the measurement of this response.
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DISCUSSION |
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Another interesting finding is the nonlinear distribution of TCDD within maternal and fetal tissues. Table 1 illustrates a dose-dependent increase in the maternal liver/adipose ratio, indicating hepatic sequestration. This is due to the induction of a hepatic binding protein, CYP1A2, by TCDD (Diliberto et al., 1997
; Santostefano et al., 1996
). A dose-dependent increase in the liver to fat ratio implies that at lower doses there is relatively more of the chemical available for extrahepatic tissues. For example, a dose of 0.05 µg TCDD/kg results in 0.51% of the administered dose present in the fetal compartment, as opposed to 0.17% administered dose after exposure to 1.0 µg TCDD/kg (Table 2
). Therefore, it is important to consider that many high-dose animal studies may underpredict extrahepatic responses at low doses.
It is important to understand the disposition of a chemical to target tissues, as this information is crucial in understanding the relationship between tissue concentration and the response. The present study investigated whether tissue concentration was an appropriate dose metric to predict adverse reproductive and developmental effects. In addition, other dose metrics should be examined for use in species extrapolation. For example, lifetime area under the curve (AUC), body burden, tissue concentration, average blood concentration, or daily dose provide a means to estimate the risk of human exposure to these compounds. For chemicals with a mechanism of action that depends on maintaining a critical tissue or blood concentration for a specific duration to elicit a toxic response, AUC is probably the appropriate dose metric (Benet et al., 1996). However, for adverse effects due to prenatal exposure, it is important to consider the critical time at which exposure occurs. Birnbaum and coworkers (1985) demonstrated that the peak period for TCDD-induced effects on palate formation in C57BL/6N mice occurs between GD11 and GD12. In addition, a single dose of 24 µg TCDD/kg administered to pregnant C57BL/6N mice increased the incidence of prenatal mortality on GD6 but did not increase mortality on GD8, 10, 12, or 14 (Couture et al., 1990
). This suggests that the sensitive window for fetal lethality in mice occurs on or before GD6. For this reason, tissue concentration during this critical period may be a better indicator of embryo toxicity.
Results from two different exposures during gestation (GD8 and GD15) show that fetal tissue concentration better predicts the intensity of the developmental abnormality as compared to administered dose. For example, Figs. 14 clearly show that the model predicts the change in ejaculated sperm counts and puberty delay in males and urethra-phallus distance and vaginal thread incidence in females based on fetal TCDD concentration on GD16 following exposure on GD8 or GD15. Although fetal TCDD tissue concentrations on GD16 following GD8 exposure slightly underpredict the incidence of vaginal thread, the discrepancy may be attributed to a block effect in the design of the reproductive studies or to the fact that GD16 is past the critical window of sensitivity for this effect. It is important to understand that tissue concentration at a critical period during gestation is the appropriate dose metric. In contrast, administered dose fails to predict the severity of the response. For example, administration of 1.0 µg TCDD/kg on GD8 produces a 14% incidence of vaginal thread in female LE pups (Gray and Ostby, 1995
) (Table 4
). However, the same dose administered on GD15 produces 79% incidence of vaginal thread (Gray and Ostby, 1995
). Therefore, administered dose poorly predicts these reproductive and developmental responses. Although other dose metrics (AUC, body burden, and blood concentration) may also be used to predict risk, results from this study clearly show that fetal tissue concentration measured during a critical period is a better measure than administered dose.
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For the reproductive and developmental effects examined in this study, fetal TCDD concentrations accurately predict the overall severity of the response. However, the usefulness of analyzing fetal concentrations is questionable in terms of assessing human health risk. Therefore, a more realistic approach to assess exposure is to determine concentrations of dioxin and dioxinlike compounds in maternal tissues or serum. On GD21, maternal body burdens were 27431 ng TCDD/kg following exposure to 0.051.0 µg TCDD/kg on GD15. These calculations are based on the assumption that 90% of the residue is located in liver, adipose, muscle, and skin. Although these types of calculations can be done in human populations, a more realistic approach would be to analyze serum concentrations of dioxinlike chemicals. For this reason, we explored the relationship between maternal and fetal TCDD tissue concentrations. On GD16 there was a significant correlation between fetal body burden and maternal body burden (1:9; r2 = 0.91, p < 0.0001). In addition, there was a strong correlation between fetal body burden and maternal blood levels (1.8:1; r2 = 0.932, p < 0.0001). These data suggest that a measurement of maternal blood levels at a critical time provides a means to estimate concentrations of dioxin within the developing fetus.
Most people are exposed to low levels of dioxins and dioxinlike compounds, which are found in the food supply. The background body burden of PCDD/PCDF/PCB in humans is 913 ng TEQ/kg body weight (DeVito et al., 1995). However, dioxin body burdens in humans are log-normally distributed and for this reason, it is likely than certain individuals contain greater concentrations (DeVito et al., 1995
; Sielkin, 1977). Several epidemiologic studies suggest a correlation between TCDD exposure and adverse outcomes. For example, a body burden of 109-7000 ng TCDD/kg is associated with increased risk of cancer (Bertazzi et al., 1993
; Fingerhut et al., 1991
). In addition, decreased birth weights and delayed developmental milestones are associated with a maternal body burden of 2130 ng TEQ/kg (Chen et al., 1992
; DeVito et al., 1995
; Lucier, 1991
; Rogan et al., 1988
). Maternal body burdens slightly above background (16 ng TEQ/kg) are associated with lower birth weight, lower psychomotor scores, and poorer neurologic condition (Huisman et al., 1995a
; Huisman et al., 1995b
; Koopman-Esseboom et al., 1994
; Koopman-Esseboom et al., 1996
; Patandin et al., 1998
). The lowest dose used in this study (0.05 µg TCDD/kg) resulted in a maternal body burden of 27 ng TCDD/kg on GD21, which is associated with accelerated eye opening and a reduction in sperm counts of male offspring (Gray et al., 1997a
). This body burden is only 23 times higher than the average background TEQ in U. S. populations.
In conclusion, TCDD induces a wide range of adverse effects in experimental animals. Epidemiologic studies indicate that humans are similar to animals in their response to dioxins, such as diminished immune function and growth and development, and carcinogenesis (Birnbaum, 1994b). Results from our study indicate that fetal tissue concentrations at a critical period of sensitivity provide a means to assess the potential for the development of adverse effects. Furthermore, concentrations of TCDD in the developing fetus are highly correlated with concentrations found in maternal blood. This indicates that maternal concentrations of TCDD would provide a means to determine fetal exposure to dioxin and the potential effects associated with this exposure. A better understanding of the relationship between tissue concentration of TCDD and the development of adverse outcomes may facilitate the ability to predict whether human populations are at risk for effects associated with low-level exposure to TCDD.
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ACKNOWLEDGMENTS |
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NOTES |
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The research described in this article has been funded in part by the U. S. Environmental Protection Agency Cooperative Training Agreement (ES07126) with the University of North Carolina at Chapel Hill, NC 275997270. The manuscript has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, U. S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or use recommendation.
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