Combining epidemiology and toxicology for the purpose of deriving ERFs: TCDD-induced dental aberrations

Submitted by marjo on Thu, 2010-04-29 12:05

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Aim: To derive a combined dose-response estimate for TCDD-induced dental aberrations based on epidemiological and toxicological data.

For this purpose, two studies were selected:

Epidemiological study: Alaluusua, S., Calderara, P., Gerthoux, P.M., Lukinmaa, P-L., Kovero, O., Needham, L., Patterson, D.G., Tuomisto, J., and Mocarelli, P. (2004) Developmental dental aberrations after the dioxin accident in Seveso. Environ Health Perspect. 112, 1313-8.

Toxicological study: Kattainen, H., Tuukkanen, J., Simanainen, U., Tuomisto, J.T., Kovero, O., Lukinmaa, P-L., Alaluusua, S., Tuomisto, J., and Viluksela, M. (2001) In utero/lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure impairs molar tooth development in rats. Toxicol Appl Pharmacol. 174, 216-24.

We selected one epidemiological study and one toxicological study (see above) on a same environmental pollutant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in order to create a combined best-estimate dose-response for a selected health effect, developmental dental aberrations, including the evaluation of the most relevant uncertainties and their size in each study. The Alaluusua et al. (2004) study was selected as a starting point, since it is the only human study on TCDD-induced dental aberrations where the exposure was determined as serum TCDD concentration. Next, we wanted to see whether the available toxicological results would support the epidemiological evidence, and selected the Kattainen et al. (2001) study on rats, since it is a dose-response study using low TCDD doses approaching the levels of human background exposure. Here we present a systematic comparison of these two studies. The following topics are considered: 1) the selected endpoints and their comparability 2) the expression of the exposure in same metrics in the two species 3) the most important sources of uncertainty identified in each study. The uncertainties were assessed with the help of correction factor table.

Explanation of the method

Explanation of the method:

Exposure and outcome considerations

Endpoint

· In humans, the endpoint was enamel defects of all teeth except the 8^th teeth in study subjects who were less than 5 years old at the time of TCDD-exposure.

· In rats, the endpoint was reduced size of or missing third molar in TCDD-sensitive line C rats. The exactly same endpoint (enamel defects) as in the human study could not be used since it was not studied. In order to calculate risk, cut-point for the normal molar size had to be decided.

TCDD-exposure

· The persons exposed to TCDD in Seveso were divided into tertiles based on serum TCDD levels, which were 31-226 (n = 10), 238-592 (n = 11) and 700-26,000 (n = 15) ng/kg (Alaluusua et al., 2004). Controls (n = 39) were from the surrounding area but their serum TCDD levels are not known. As control exposure, we used the background serum TCDD levels measured from two pooled samples of 40 children (0-12 years old) from the surrounding non-ABR area in an another study (Eskenazi et al., 2004). These values were 33.4 and 47.6 ng/kg. As the TCDD levels of the lowest tertile of the exposed overlapped the background exposure, the lowest tertile and the controls were grouped (n = 49) for the analysis of risk.

· In the rat study, the maternal dose is exactly known. It was converted to the concentration in the pup. Matters that were considered:

- Which developmental time-point in the pups would best correspond to the time window when humans were exposed? Considerations were made on teeth development and its most sensitive phases in the two species. Subsequently, it was deduced that TCDD-concentration on postexposure day 7 would best correspond the time-window of human exposure.

- How to convert the known maternal TCDD-dose to the concentration in the pup at postexposure day 7? This was done with the help of another study (Miettinen et al., 2005) where the concentration in the offspring was measured on post-natal days 0 and 5 after the maternal dose of 0.5 µg/kg. Another matter is that the proportion of TCDD transferred from dam to pup is not constant but dependent on the dose (Hurst et al., 2000) in a way that smaller proportion of higher doses is transferred to fetus than of lower doses at least in the dose range of 0.05 to 0.8 µg/kg. Based on this knowledge, the correction factors to be used in calculating the pup concentrations on postexposure day 7 were determined.

Results

Risk for dental aberrations

In the Seveso study, significant exposure (238-592 pg/g or 700-26,000 pg/g in serum lipid) to TCDD increased the risk for dental aberrations in humans 2.1 and 2.7 fold, respectively. In line C rats, the lowest exposure causing the estimated TCDD concentration of 501 pg/g lipid on PND7 had a small influence on the risk for dental aberrations (risk ratio 1.2). The higher TCDD exposures of 1437 and 3010 pg/g lipid increased the risk for smaller/missing third molars 8.5 and 11.5 fold, respectively, and the highest TCDD exposure (6220 pg/g lipid) 15.0 fold.

The most important uncertainties identified

The rat study:

· Toxicodynamics between rat and human. This relates to pathways through which TCDD affects dental development. Although the effect most probably is mediated by the aryl hydrocarbon receptor, it is not known whether the downstream pathways are the same in both species.

· Endpoint extrapolation. It is not known which endpoint in rats would most perfectly represent the enamel defects seen in humans. It is unclear how close from the mechanistic point of view are the enamel defects in humans and the reduced tooth size in rats, however, according to Miettinen et al. (2002) the dental epithelium, which forms the enamel part of the tooth, is the likely target of TCDD in rats. Therefore it seems that the enamel is the major dental target of TCDD in both species.

· Exact concentration of TCDD in the pups. This was deduced using some justified assumptions (see above).

The human study:

· Exposure misclassification. Serum TCDD concentration of the controls was not assessed. Part of the persons considered exposed had serum TCDD levels overlapping the background exposure.

Conclusions

The current synthesis of toxicological and epidemiological data supports the view that TCDD´s ability to induce dental aberrations is comparable in rats and humans, the latter species possibly being even more sensitive. A combined dose-response function is still under development.

Integrated Environmental Health Impact Assessment System

Combining epidemiology and toxicology for the purpose of deriving ERFs: TCDD-induced dental aberrations

Exposure and outcome considerations

Results

Conclusions

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