Issues in Risk Assessment for Developmental Effects of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin and Related Compounds

Lesa L. Aylward*,1, James C. Lamb{dagger} and Steven C. Lewis{ddagger}

* Exponent, Inc., Alexandria, Virginia 22314; {dagger} The Weinberg Group, Washington, DC 20036-2400; and {ddagger} Integrative Policy & Science, Inc., Washington, New Jersey 07882

1 To whom correspondence should be addressed at Exponent, Inc., 1800 Diagonal Road, Suite 300, Alexandria, VA 22314. Fax: (571) 227-7299. E-mail: laylward{at}exponent.com.

Received March 2, 2005; accepted June 15, 2005


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERNAL-FETAL DISTRIBUTION...
 APPLICATION OF TEF/TEQ APPROACH...
 INTRINSIC INTERSPECIES...
 CONCLUSIONS AND RESEARCH NEEDS
 REFERENCES
 
Recent risk assessments for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds have focused on adverse effects observed in rodent offspring exposed while in utero during critical gestational periods as among the most sensitive adverse effects attributable to TCDD exposure. In addition, these risk assessments have converged on the use of body concentration (or "body burden") of TCDD as a dose metric superior to administered dose for cross-species comparisons and risk assessments, due to the interspecies differences in elimination kinetics and substantial persistence of these compounds. The detailed, although incomplete, data that are available on maternal–fetal distribution of TCDD and related compounds illustrate differences in distribution among these compounds that impact assessments on a body-burden basis. These data also demonstrate differences in distribution after subchronic or chronic administration compared to acute administration. Some data are now also available addressing inconsistencies that may arise from the use of TCDD toxic equivalency factors (TEFs), which were derived on an administered-dose basis, in evaluating responses to mixtures of dioxins on a body-burden basis in the context of chronic exposure situations. Finally, the use of body burden as a dose metric does not account for or eliminate the substantial differences in sensitivity to dioxin observed across species or between different strains of the same species and, thus, does not eliminate the need to consider the relative sensitivity of humans compared to laboratory animal models in risk assessments. Additional research areas that may increase the foundation for interspecies extrapolations are discussed.

Key Words: TCDD; 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEF; TEQ; risk assessment.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERNAL-FETAL DISTRIBUTION...
 APPLICATION OF TEF/TEQ APPROACH...
 INTRINSIC INTERSPECIES...
 CONCLUSIONS AND RESEARCH NEEDS
 REFERENCES
 
Several U.S. and international groups have conducted recent risk assessments for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. The World Health Organization/UN Food and Agriculture Agency Joint Expert Committee on Food Additives (JECFA, 2001Go) and the European Commission Scientific Committee on Food (ECSCF, 2001Go) published assessments of tolerable intake levels for dioxins within a few months of each other in 2001, while the USEPA published another draft of its dioxin risk assessment in 2003. All of these assessments focus on a body of data that indicates that the most sensitive adverse responses to TCDD in experimental animal studies appear to be effects on the development of offspring following in utero exposure to TCDD.

In these and other recent assessments of dioxin toxicity and risk, the body concentration (or "body burden") of dioxin has been identified and used widely as a dose metric for assessment of dioxin response, one that is deemed superior to administered dose for interspecies comparisons (Birnbaum and Tuomisto, 2000Go; ECSCF, 2001Go; JECFA, 2001Go). The kinetics for elimination of TCDD and other dioxin-like compounds vary widely among species (Van den Berg et al., 1994Go). For example, the apparent first-order half-life for elimination of TCDD in rats is on the order of 25 days, while in humans at background exposure levels, it is approximately 100 times as long. The slower elimination in humans results in a correspondingly greater accumulation of the compounds after chronic administration compared to the accumulation in rodents. Given the wide variation in elimination kinetics among species, the use of body burden as a dose metric for evaluation and comparison of responses to dioxin is attractive, because it may provide a more toxicologically relevant basis than administered dose for comparing responses among species, particularly following chronic exposure. However, the use of body burden as a dose metric is not a substitute for consideration of several key issues, including:

This article provides a critical review of the factors impacting the interpretation and extrapolation to humans of the available toxicological data on low-dose adverse effects on development of offspring following in utero exposure to TCDD.


    MATERNAL-FETAL DISTRIBUTION ISSUES: VARIATIONS DUE TO DOSING REGIMEN AND AMONG CONGENERS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERNAL-FETAL DISTRIBUTION...
 APPLICATION OF TEF/TEQ APPROACH...
 INTRINSIC INTERSPECIES...
 CONCLUSIONS AND RESEARCH NEEDS
 REFERENCES
 
In general, the most sensitive adverse effect endpoints identified and evaluated in recent dioxin risk assessments are alterations in male rat reproductive system parameters following acute TCDD administration to dams on gestation day 15 (ECSCF, 2001Go; JECFA, 2001Go; UKCOT, 2001Go; USEPA, 2003Go). However, the database on these and related endpoints in rats or mice is incomplete, because no studies of these effects resulting from chronic rather than acute administration of either TCDD or representative TEQ mixtures exist. Instead, the risk assessments based on these data rely on maternal body burden of TCDD as the appropriate measure of exposure, combined with extrapolation of these results in two ways:

Recent data on differential organ and tissue distribution among congeners after either acute or chronic administration have not been fully accounted for in these extrapolations in risk assessments conducted to date (Hurst et al., 2000aGo,bGo). Recent studies in laboratory rats provide substantial data showing wide variations in maternal–fetal distribution patterns among TCDD and related compounds and following chronic versus acute gestation day 15 administration (Chen et al., 2001Go). Some of these data are highlighted in the text and figures below.

  1. Distribution of TCDD to the fetus on gestation day 16 after chronic maternal administration is much less efficient than after acute administration on gestation day 15 (Fig. 1). Distribution of TCDD to the fetus as a fraction of maternal body burden after subchronic exposure is two- to three-fold lower than that observed after acute administration, and the difference in transfer rates is greatest at the lowest dose levels, which are most relevant to background exposure (Hurst et al., 2000aGo,bGo). These data were incorporated into the evaluations by JECFA (2001)Go and ECSCF (2001)Go. In these evaluations, the NOAEL and LOAEL values from studies using acute exposure regimens were adjusted upward to account for attenuation of fetal distribution likely to result from body burdens arising from chronic exposure to the dam.
  2. Distribution of a mixture of nine TEQ contributors (including substantial proportions of TCDD and PCB 126) to the fetus on gestation day 16 is much less efficient than transfer of pure TCDD after acute administration on gestation day 15 or subchronic maternal TCDD administration (Fig. 1). The ratio of fetal to maternal TEQ body burden is approximately four-fold lower than the corresponding ratio from the study of TCDD administration alone (Chen et al., 2001Go). The difference in fetal transfer is apparent when the distribution to the fetus is examined on a congener-specific basis (Fig. 2). Every other tested congener is distributed to the fetus less efficiently than TCDD, and most are transferred at only a small fraction of the efficiency of TCDD. These data were not available at the time of the ECSCF (2001)Go and JECFA (2001)Go evaluations and were not included in the USEPA (2003)Go evaluations.
  3. The tested TEQ mixture in Chen et al. (2001)Go results in a different pattern of maternal body burden than is seen in typical U.S. background body burdens and probably overpredicts the transfer of a mix more typical of U.S. background (Figs. 3 and 4). TCDD and PCB 126 account for nearly 80% of the maternal body burden at the lowest tested dose in Chen et al. (2001)Go, but account for less than 20% of typical U.S. body burdens. For the two congeners that together constitute nearly 40% of U.S. body burdens (PeCDD and 4-PeCDF), fetal transfer was approximately ten-fold less efficient than for TCDD and PCB 126 at the lowest (and most relevant) tested dose (Fig. 4). The congener group that is most prominent in U.S. background body burdens, HxCDDs, was not included in the Chen et al. (2001)Go study.



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FIG. 1. Ratio of fetal to maternal body burdens in Long-Evans rats on gestation day 16 across a range of doses. Data from Hurst et al. (2000b)Go study of acute administration of TCDD on gestation day 15; Hurst et al. (2000a)Go study of subchronic administration of TCDD; and Chen et al. (2001)Go study of acute administration of a mixture of TEQ contributors on gestation day 15. Maternal and fetal body burdens are represented either as reported by the authors (Hurst et al. 2000aGo,bGo) or were estimated using reported liver and adipose tissue burdens. Fetal burdens were reported by the authors. Transfer of TCDD to the fetus as a fraction of maternal body burden was much lower after subchronic administration than after acute administration. Transfer of a TEQ mixture to the fetus following acute maternal administration was less efficient still, with fetal transfer approximately four-fold less efficient than after acute administration of TCDD. No data are available to document distribution of a TEQ mixture to the fetus following subchronic maternal exposure to a TEQ mixture.
 


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FIG. 2. Congener-specific ratios of fetal to maternal body burdens in Long-Evans rats on gestation day 16 from Chen et al. (2001)Go for four dose groups (nominal TEQ dose levels) after acute administration of a mixture of TEQ contributors on gestation day 15. Fetal body burdens were reported by the authors; maternal body burdens were estimated as the sum of liver and adipose burdens. The overall TEQ transfer was heavily influenced by the transfer of TCDD and PCB 126, which together accounted for nearly 80% of the maternal body burden on gestation day 16 in this study. Fetal transfer of all other tested compounds was less efficient than the transfer of TCDD.
 


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FIG. 3. Comparison of maternal body burden TEQ contributors from Chen et al. (2001)Go (maternal body burdens in Long-Evans rats on gestation day 16 following acute administration on gestation day 15, lowest dose group) with pattern of congeners in typical U.S. background populations. Nearly 80% of the maternal TEQ body burdens in the Chen et al. (2001)Go study are due to TCDD and PCB 126, while these two compounds account for less than 20% of U.S. background body burdens. The U.S. background body burden profile was taken from a report of CDC data presented in USEPA (2003Go, Part I, Volume II, p. 4–96).
 


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FIG. 4. Ratio of fetal to maternal body burdens in Long-Evans rats on gestation day 16 from Chen et al. (2001)Go for the top five contributors to human background body burdens. Chen et al. (2001)Go did not include any HxCDD congeners, which are the largest contributors to U.S. background body burdens. The next two largest contributors to human body burdens, PeCDD and 4 PeCDF, showed very low transfer of compounds to the fetus in the Chen et al. (2001)Go study. The two congeners with the highest ratio of fetal to maternal body burdens in the Chen et al. (2001)Go study, TCDD and PCB 126, constitute less than 20% of U.S. background body burdens but constituted 80% of the maternal body burdens in the Chen et al. (2001)Go study.
 
The lower fetal transfer of non-TCDD congeners is probably due to differential maternal distribution (Fig. 5). Nearly all of the other tested congeners in Chen et al. (2001)Go have much higher affinity for hepatic tissue, relative to adipose tissue, than TCDD. This pattern of differential hepatic sequestration among congeners in rodents has been understood for some time (reviewed in Van den Berg et al., 1994Go). This hepatic sequestration probably reduces the proportion of maternal body burden that is available for transfer to the fetus. In addition, maternal hepatic sequestration may be more pronounced after chronic administration, compared to acute administration, because chronic administration would allow for increased induction of the CYP1A2 binding protein in maternal liver. However, data do not exist to confirm this potential effect of chronic versus acute administration on distribution to the fetus.



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FIG. 5. Ratio of maternal liver to adipose concentration in Long-Evans rats on gestation day 16 after acute administration of a mixture of TEQ contributors at the lowest tested dose, 50 ng TEQ/kg (Chen et al. 2001Go). All but one of the tested compounds had higher liver-to-adipose concentration ratios than TCDD, indicating increased hepatic sequestration of these compounds compared to TCDD and the likelihood that a lower proportion of the maternal body burden is available for transfer to the fetus compared to TCDD.

 
It is important to keep the actual magnitude of the "low" doses used in these studies in perspective; the lowest single maternal dose of TCDD used in these studies is approximately 100,000 times greater than the daily TEQ intake dose to which humans are exposed from the diet. The physiological and toxicological response to a bolus dose may well be substantially different from the response to a slowly accumulating, essentially steady-state body burden, even at the same instantaneous body burden, for a variety of pharmacokinetic and pharmacodynamic reasons, particularly during a sensitive and dynamic physiological period such as gestation.

Based on the available data, it is clear that there is a need for a comprehensive study of these endpoints and fetal distribution of these compounds employing chronic administration (preferably through diet, in order to mimic human exposure patterns) of a TEQ mixture that results in maternal body burdens with a congener pattern similar to that observed in the general population (that is, not dominated by TCDD). Based on the data to date, the fetal exposure after subchronic acute administration of TCDD is two- to three-fold lower than the fetal exposure resulting from acute maternal exposure to TCDD. In addition, distribution to the fetus following acute maternal exposure on gestation day 15 of a TEQ mixture is substantially lower than the fetal exposure following acute exposure to pure TCDD (at least four-fold lower). The combined impact of these two extrapolations suggests that the maternal body burdens in studies of acute TCDD administration on gestation day 15 may be four- to ten-fold lower than the chronic maternal body burdens of a representative TEQ mixture that would be required to result in equivalent distribution to the fetus in this animal model. Direct extrapolation of the results of the studies of acute administration of TCDD to the general population exposure situation of chronic human exposure to a TEQ mixture consisting primarily of non-TCDD congeners on a maternal body-burden basis may overstate substantially the risk of current maternal TEQ body burdens in the general population.


    APPLICATION OF TEF/TEQ APPROACH TO BODY-BURDEN-BASED ASSESSMENTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERNAL-FETAL DISTRIBUTION...
 APPLICATION OF TEF/TEQ APPROACH...
 INTRINSIC INTERSPECIES...
 CONCLUSIONS AND RESEARCH NEEDS
 REFERENCES
 
Recent risk assessments of dioxins have, by necessity, relied almost exclusively on studies of exposure to TCDD alone (rather than TEQ mixtures) in combination with a body-burden dose metric for hazard assessment. The results of the hazard assessments, whether for cancer or noncancer endpoints, have been extended to predict risks to the human population due to a mixture of TCDD (accounting for 10% of TEQ) and other TEQ-contributing compounds, again on a body-burden basis. In some cases these body-burden-based assessments have been reconverted to equivalent intake doses, but the extrapolations and applications of uncertainty factors have been conducted on a body-burden basis. However, the TEF/TEQ scheme was explicitly developed based on assessment of the results of studies comparing potency between individual compounds and TCDD on an administered-dose basis (Van den Berg et al., 1998Go). The pharmacokinetics of the various TEQ-contributing compounds vary widely, as do the distribution patterns of these compounds, and the relative kinetics among different congeners can be different in different species (Van den Berg et al., 1994Go). This was accounted for in the derivation of the TEF values on an administered-dose basis.

However, a logical result of the differences among congeners in pharmacokinetics is that, under conditions of chronic exposure, the relationship between body burden or tissue concentration and response may be quite different from the relationship between administered dose and response, and the potencies relative to TCDD may shift among the different compounds.

For example, DeVito et al. (1997)Go, in a study in mice of disposition and enzyme induction potency for several dioxin and furan congeners, compared potency on the basis of both administered dose and tissue concentration and found significant differences in the two approaches. Based on their results, they concluded that:

These data suggest that two sets of TEF values may be useful in estimating risk of dioxinlike compounds. One set of values would be used for estimating intake equivalents and the other for estimating tissue equivalents.

The effect of this issue can be seen when examining the results of the recent 2-year National Toxicology Program carcinogenicity bioassays of TCDD, 4-PeCDF, PCB-126, and a mixture of the three (NTP, 2004aGo,bGo,cGo,dGo). Walker et al. (2005)Go have reported that for some of the tumor endpoints, the TEF/TEQ approach works reasonably well on an administered-dose basis. That is, the degree of tumor response is similar across the various compounds and the mixture for TEQ-equivalent administered doses (although 4-PeCDF showed little tumor response at any dose, and its potency was consistently overpredicted by its TEF). However, the body burdens on a TEQ basis in these four bioassays vary dramatically. For TEQ-equivalent administered doses, the lifetime average TEQ body burdens in the 4-PeCDF, PCB 126, and TEQ mixture bioassays are approximately seven-fold, three-fold, and four-fold higher than in the TCDD bioassay, respectively. This indicates that the two tested compounds other than TCDD and the TEQ mixture, on a TEQ body-burden basis, are at least several-fold less potent as carcinogens than TCDD. That is, on a body-burden basis, the TEQ approach over-predicts the carcinogenicity of these compounds. This result is consistent with an earlier subchronic liver tumor promotion study which found that, on a tissue-concentration basis, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD) and 4-PeCDF had substantially lower potencies relative to TCDD than when assessed on an administered-dose basis (Waern et al., 1991Go).

The practice of measuring the concentrations of PCDD/Fs in human serum lipid and converting those concentrations to TEQs has become routine, yet this conversion process explicitly applies relative toxicity estimates based on administered doses (the TEFs) to tissue concentrations to express serum lipid concentrations in TCDD "toxic equivalents." The recent cancer bioassay data from NTP highlight the pitfalls that can arise when the current TEFs, which were developed through comparisons of potency on an administered-dose basis, are applied to assessing and extrapolating risk on a body-burden or tissue-concentration basis.

Data available to date indicate that, for the risk endpoints of interest (developmental effects and, in the U.S., carcinogenic risk), the TEQ scheme consistently and substantially overpredicts the activity of TEQ mixtures compared to TCDD alone on a body-burden or tissue-concentration basis. The International Programme on Chemical Safety, in coordination with the WHO, has recognized the emergence of this issue and the availability of new data and plans to explicitly address this topic at a meeting during the summer of 2005.


    INTRINSIC INTERSPECIES DIFFERENCES IN SENSITIVITY
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 ABSTRACT
 INTRODUCTION
 MATERNAL-FETAL DISTRIBUTION...
 APPLICATION OF TEF/TEQ APPROACH...
 INTRINSIC INTERSPECIES...
 CONCLUSIONS AND RESEARCH NEEDS
 REFERENCES
 
A hallmark of the toxicology of TCDD is substantial variability in sensitivity in response to TCDD among species and even among strains within a species. While differences in toxicokinetics (and thus, the resulting body burden from a given chronic intake dose) account for some portion of interspecies and strain differences in sensitivity, use of a body burden dose metric or adjustment for toxicokinetic differences does not eliminate or even meaningfully reduce these differences. Sensitivity to dioxin for specific endpoints can vary by orders of magnitude, even among different strains of mice and rats (Shen and Olson, 1987Go; Tuomisto et al., 1999Go).

This can be illustrated by comparing benchmark dose modeling results on developmental endpoints for rats and mice presented by the USEPA (2003Go; Appendix III to Chapter 8 of Part II). Using the 34 data sets for which the endpoint of interest displayed a significant response at some tested dose and for which the EPA benchmark dose model gave an acceptable fit, the range of benchmark dose estimates for a 1% response level (ED01) for two species can be compared (Fig. 6). These data sets consist of 16 mouse and 18 rat developmental endpoints (with some overlap in endpoints across the two species) observed subsequent to single-dose administration of TCDD to dams at critical periods during gestation. Because these are single-dose studies, the maternal body burdens during the critical developmental periods are completely correlated with the administered doses and are not affected by the somewhat different kinetics between rats and mice. That is, a single dose of 100 ng/kg on the critical gestational day is presumed to result in a similar peak maternal body burden in both species, regardless of subsequent elimination rates. However, the responsiveness is substantially different between these two species.



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FIG. 6. Plot of EPA-modeled ED01 values for mice and rats for developmental endpoints in mice (n = 16) and rats (n = 18) following administration of a single dose (ng/kg maternal bodyweight) of TCDD to dams during critical periods of gestation. Because these are single-dose studies, the peak maternal body burden on the critical gestational day for each study is directly correlated with the single administered dose on a ng/kg bodyweight basis (i.e., peak body burden would differ from the administered dose only to the extent that the doses are not fully absorbed). Median ED01 values for the two species are indicated by the horizontal bars. The plotted ED01 values are based on EPA's benchmark dose modeling procedure, rather than risk-based benchmark doses. The median ED01 for these endpoints in mice, 3300 ng/kg, is more than 300 times greater than the corresponding median in rats, 10.5 ng/kg, and all benchmark doses for mice are above the median benchmark dose for rats, illustrating a fundamental difference in sensitivity to TCDD between mice and rats.

 
The median modeled ED01 value for the two species differs by a factor of more than 300 (Fig. 6). The modeled mouse ED01 values are all higher than the median rat ED01 value. These data sets illustrate that large interspecies differences in sensitivity to TCDD exist, even when body burden is used as the dose metric for comparison among species. Such interspecies variability still must be taken into account in extrapolations of risk among species, even when body burden is used as the dose metric.

Recent risk assessments for dioxin have acknowledged the variability in species sensitivity and the likelihood that humans are in the mid-range of sensitivity (ECSCF, 2001Go; JECFA, 2001Go). For example, the USEPA (2003)Go stated that:

It is well known that individual species vary in their sensitivity to any particular dioxin effect.... However, the evidence available to date indicates that humans most likely fall in the middle rather than at either extreme of the range of sensitivity for individual effects among animals. In other words, evaluation of the available data suggests that humans, in general, are neither extremely sensitive nor insensitive to the individual effects of dioxin-like compounds (Part III, p. 62).

The basis for interspecies differences is almost certainly multifactorial. One source of differences in sensitivity among strains and species has been identified. The DBA mouse is at least 10-fold less sensitive than the C57 mouse to the toxic effects of TCDD. The Ah receptor (AhR) of the DBA mouse carries two key mutations compared to that of the C57 mouse, one each in the binding domain and the transactivation domain. As a result, the AhR of the DBA mouse has a lower affinity for TCDD binding, and the bound receptor-ligand complex is less efficacious in producing toxicity (reviewed in Connor and Aylward, in pressGo). Humans share the same two key mutations in the AhR, and these mutations convey the same reduction in responsiveness to TCDD compared to C57 mice in a humanized chimeric mouse model in which a human AhR was inserted into a C57 AhR-knockout mouse (Moriguchi et al., 2003Go). The human AhR exhibits some polymorphisms, but the polymorphisms observed to date have not involved the key binding and transactivation domain mutations and have not been correlated with binding affinity (Harper et al., 2002Go; Nebert et al., 2004Go; Okey et al., 2005Go).

In addition, more recent research using gene-sequencing techniques has demonstrated interspecies differences in the numbers and identities of dioxin-responding genes. The human genome contains fewer than 40% of the active dioxin-responding genes found in mice and rats (Sun et al., 2004Go), raising the possibility that, in addition to quantitative reductions in sensitivity in humans due to the generally low-affinity AhR present in humans, there is a reduction in the number of responding genes in humans compared to the laboratory rodents. Depending on the specific differences in responding genes between rodents and humans, this reduction in responding genes could have a direct effect on toxic responses. These authors conclude that this research is likely to "fuel the debate regarding the suitability of rodent models to assess the potential human health risks associated with exposure to AhR ligands" (Sun et al., 2004Go, p. 4522).

These data suggest that direct extrapolation of the most sensitive adverse responses from sensitive rodent species to humans may be unnecessarily conservative. The ECSCF (2001)Go and JECFA (2001)Go risk assessments incorporated this understanding by applying minimal interspecies uncertainty factors to the most sensitive rodent responses evaluated on a body-burden basis in their derivations of tolerable daily intakes. While the conventional approach to risk assessments may suggest a reliance on the most sensitive laboratory species in order to be protective of sensitive human subpopulation, the use of additional uncertainty factors in risk assessment for variations in human sensitivity may not be necessary if this approach is adopted for dioxin, because the most sensitive human may be less sensitive than the most sensitive rodents.


    CONCLUSIONS AND RESEARCH NEEDS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERNAL-FETAL DISTRIBUTION...
 APPLICATION OF TEF/TEQ APPROACH...
 INTRINSIC INTERSPECIES...
 CONCLUSIONS AND RESEARCH NEEDS
 REFERENCES
 
The focus of recent risk assessments for dioxin on potential adverse effects to offspring from in utero exposure to dioxins is appropriate. However, quantitative extrapolation of the animal data on these endpoints to potential human risks and in the context of identifying tolerable daily intakes should take into account the full range of available detailed data on kinetics and distribution, on interspecies sensitivity, and on the appropriateness of the TEF approach for body burden-based assessments. The rich database available on TCDD and related compounds, while still lacking key studies, allows a critical evaluation and possible modification of the conventional risk assessment assumptions for interspecies extrapolation. The available data on maternal to fetal transfer of non-TCDD congeners, the importance of dose regimen, limitations in the TEF approach on a body-burden basis, and interspecies differences in sensitivity suggest that these conventional assumptions may result in overly conservative estimates of risk from general population exposures to dioxins.

Numerous areas of research could increase the reliability of and scientific foundation for risk extrapolations from animals to humans for dioxins.


    ACKNOWLEDGMENTS
 
Funding for this review was provided by the Chlorine Chemistry Council. Conflict of interest: none declared.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERNAL-FETAL DISTRIBUTION...
 APPLICATION OF TEF/TEQ APPROACH...
 INTRINSIC INTERSPECIES...
 CONCLUSIONS AND RESEARCH NEEDS
 REFERENCES
 
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DeVito, M. J., Diliberto, J. J., Ross, D. G., Menache, M. G., and Birnbaum, L. S. (1997). Dose-response relationships for polyhalogenated dioxins and dibenzofurans following subchronic treatment in mice. I. CYP1A1 and CYP1A2 enzyme activity in liver, lung, and skin. Toxicol. Appl. Pharmacol. 147, 267–280.[CrossRef][ISI][Medline]

European Commission Scientific Committee on Foods (ECSCF) (2001). Opinion of the Scientific Committee on Food on the risk assessment of dioxins and dioxin-like PCBs in food. Update based on new scientific information available since the adoption of the SCF opinion of 22nd November 2000. Rep. CS/CNTM/DIOXIN/20 final. European Commission Scientific Committee on Foods, Brussels, Belgium. Avaliable at: http://europa.eu.int/comm/food/fs/sc/scf/out90_en.pdf.

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Hurst, C. H., DeVito, M. J., Setzer, R. W., and Birnbaum, L. S. (2000b). Acute administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in pregnant Long Evans rats: Association of measured tissue concentrations with developmental effects. Toxicol. Sci. 53, 411–420.[Abstract/Free Full Text]

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Moriguchi, T., Motohashi, H., Hosoya, T., Nakajima, O., Takahashi, S., Ohsako, S., Aoki, Y., Nishimura, N., Tohyama, C., Fujii-Kuriyama, Y., et al. (2003). Distinct response to dioxin in an arylhydrocarbon receptor (AHR)-humanized mouse. Proc. Natl. Acad. Sci. U.S.A. 100, 5652–5657.[Abstract/Free Full Text]

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